Combinations of beta-lactam compounds and probenecid and uses thereof

ABSTRACT

The present disclosure relates to bilayer tablets comprising a second layer comprising a β-lactam compound or a pharmaceutically acceptable salt thereof; and a first layer comprising probenecid or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods of treating or preventing a disease using the bilayer tablets.

RELATED APPLICATION

This application claims priority to, and the benefit of, U.S.Provisional Application No. 62/804,973, filed Feb. 13, 2019, the entirecontents of which is incorporated herein by reference.

BACKGROUND

β-lactam compounds are a class of antibiotics having a beta-lactam ringin their molecular structures. β-lactam compounds have been used in thetreatment of diseases associated with Gram-positive and Gram-negativebacteria. The mechanism of action of these β-lactam compounds requires,optimally, that concentrations of the antibiotic remain at or above acertain inhibitory threshold, known as the ‘minimum inhibitoryconcentration (MIC)’ in order to be effective. Keeping these antibioticconcentrations elevated also helps avoid the potential for antibacterialresistance due to the selection of bacteria with higher MIC's. There is,therefore, a need for compositions and methods related to β-lactamantibiotics that optimize their tissue concentrations in order toimprove their ability to control an infection as well as alleviate oreliminate the potential for antibiotic resistance.

SUMMARY

The present disclosure provides, inter alia, a bilayer tabletcomprising: a first layer comprising probenecid or the pharmaceuticallyacceptable salt thereof, and a second layer comprising the β-lactamcompound or the pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides a method of preparing abilayer tablet, comprising:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force, therebyforming a pre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force, thereby forming a pre-coated bilayertablet.

In some aspects, the present disclosure provides a bilayer tablet beingprepared by a method of disclosed herein.

In some aspects, the present disclosure provides a method of treating orpreventing a disease, comprising administering to a subject in needthereof a bilayer tablet described herein.

In some aspects, the present disclosure provides a bilayer tabletdescribed herein for use in treating or preventing a disease in asubject in need thereof.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting. In the case ofconflict between the chemical structures and names of the compoundsdisclosed herein, the chemical structures will control.

Other features and advantages of the disclosure will be apparent fromthe following detailed description and claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram describing an exemplary process of preparing thegranular material of probenecid.

FIG. 2 is a diagram describing an exemplary process of preparing thegranular material of Compound III-2b.

FIG. 3 is a diagram describing an exemplary process of preparing thebilayer tablet of the present disclosure.

FIGS. 4A-4D are a set of diagrams comparing the in vitro releasecharacteristics of exemplary batches of the bilayer tablet of thepresent disclosure and a comparable composition. FIG. 4A is a diagramcomparing the in vitro release of probenecid for Batch Nos. 1-3 of thebilayer tablet and a comparable commercial tablet of probenecid. FIG. 4Bis a diagram showing the in vitro release of the β-lactam compound(Compound III-2b) and probenecid for Batch No. 4 of the bilayer tablet.FIG. 4C is a diagram showing the in vitro release of the β-lactamcompound (Compound III-2b) and probenecid for Batch No. 5 of the bilayertablet. FIG. 4D is a diagram showing the in vitro release of theβ-lactam compound (Compound III-2b) and probenecid for Batch No. 6 ofthe bilayer tablet.

FIGS. 5A-5G are a set of diagrams comparing several physical propertiesand in vitro release characteristics of the bilayer tablets preparedwith various first and second compression forces. FIG. 5A is a diagramcomparing the total volume of the bilayer tablets. FIG. 5B is a diagramcomparing the porosity of the bilayer tablets. FIG. 5C is a diagramcomparing the total pore surface area of the bilayer tablets. FIG. 5D isa diagram comparing the total pore count of the bilayer tablets. FIG. 5Eis a diagram comparing the volume of the largest pore of the bilayertablets. FIG. 5F is a diagram comparing the volume ratio between thelargest pore and the total pore of the bilayer tablets. FIG. 5G is adiagram showing the in vitro release characteristics of an exemplarybatch of bilayer tablets prepared by high compression force.

FIG. 6 is a diagram showing the effect of administrating the β-lactamcompound (Compound III-2b) and probencid in a bilayer tablet (ascompared to in separate formulations) in the fasted state on the plasmalevel of the β-lactam compound (Compound IIb).

FIG. 7 is a diagram showing the effect of administrating the β-lactamcompound (Compound III-2b) and probencid in a bilayer tablet (ascompared to in separate formulations) in the fed state on the plasmalevel of the β-lactam compound (Compound IIb).

FIG. 8 is a graph showing the effect of administering a β-lactamcompound (Compound III-2b) and probenecid in a bilayer tablet (ascompared to in separate formulations) on the area under the curve (AUC)for the β-lactam compound (Compound IIb).

FIG. 9 is a graph showing the effect of administering a β-lactamcompound (Compound III-2b) and probenecid in a bilayer tablet (ascompared to in separate formulations) on the maximum plasmaconcentration (C_(max)) for the β-lactam compound (Compound III-2b).

DETAILED DESCRIPTION

The present disclosure provides, inter alia, a bilayer tablet,comprising:

a second layer comprising the β-lactam compound or the pharmaceuticallyacceptable salt thereof; and

a first layer comprising probenecid or the pharmaceutically acceptablesalt thereof.

In some embodiments, the first layer comprises from 20 mg to about 5 g,from about 50 mg to about 2 g, from about 80 mg to about 1 g, from about100 mg to about 900 mg, from about 200 mg to about 800 mg, from about300 mg to about 700 mg, from about 400 mg to about 600 mg, from about450 mg to about 550 mg, or from about 480 mg to about 520 mg ofprobenecid or the pharmaceutically acceptable salt thereof.

In some embodiments, the second layer comprises from 20 mg to about 5 g,from about 50 mg to about 2 g, from about 80 mg to about 1 g, from about100 mg to about 900 mg, from about 200 mg to about 800 mg, from about300 mg to about 700 mg, from about 400 mg to about 600 mg, from about450 mg to about 550 mg, or from about 480 mg to about 520 mg of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof.

In some embodiments, the first layer comprises about 500±1000 mg, about500±900 mg, about 500±800 mg, about 500±700 mg, about 500±600 mg, about500±500 mg, about 500±450 mg, about 500±400 mg, about 500±350 mg, about500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about500±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about500±15 mg, about 500±10 mg, or about 500±5 mg of probenecid or thepharmaceutically acceptable salt thereof.

In some embodiments, the second layer comprises from 20 mg to about 5 g,from about 50 mg to about 2 g, from about 80 mg to about 1 g, from about100 mg to about 900 mg, from about 200 mg to about 800 mg, from about300 mg to about 700 mg, from about 400 mg to about 600 mg, from about450 mg to about 550 mg, or from about 480 mg to about 520 mg of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof; and the firstlayer comprises from 20 mg to about 5 g, from about 50 mg to about 2 g,from about 80 mg to about 1 g, from about 100 mg to about 900 mg, fromabout 200 mg to about 800 mg, from about 300 mg to about 700 mg, fromabout 400 mg to about 600 mg, from about 450 mg to about 550 mg, or fromabout 480 mg to about 520 mg of probenecid or the pharmaceuticallyacceptable salt thereof.

In some embodiments, the second layer comprises about 500±1000 mg, about500±900 mg, about 500±800 mg, about 500±700 mg, about 500±600 mg, about500±500 mg, about 500±450 mg, about 500±400 mg, about 500±350 mg, about500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about500±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about500±15 mg, about 500±10 mg, or about 500±5 mg of the β-lactam compound(e.g., Compound III-2, Compound III-2a, or Compound III-2b) or thepharmaceutically acceptable salt thereof.

In some embodiments, the first layer comprises about 500±1000 mg, about500±900 mg, about 500±800 mg, about 500±700 mg, about 500±600 mg, about500±500 mg, about 500±450 mg, about 500±400 mg, about 500±350 mg, about500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about500±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about500±15 mg, about 500±10 mg, or about 500±5 mg of probenecid or thepharmaceutically acceptable salt thereof, and the second layer comprisesabout 500±1000 mg, about 500±900 mg, about 500±800 mg, about 500±700 mg,about 500±600 mg, about 500±500 mg, about 500±450 mg, about 500±400 mg,about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg,about 500±150 mg, about 500±100 mg, about 500±90 mg, about 500±80 mg,about 500±70 mg, about 500±60 mg, about 500±50 mg, about 500±45 mg,about 500±40 mg, about 500±35 mg, about 500±30 mg, about 500±25 mg,about 500±20 mg, about 500±15 mg, about 500±10 mg, or about 500±5 mg ofthe β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof.

In some embodiments, the first layer comprises about 500 mg ofprobenecid or the pharmaceutically acceptable salt thereof.

In some embodiments, the second layer comprises about 500 mg of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof.

In some embodiments, the first layer of the bilayer tablet comprisesabout 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg,about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, orabout 1 g of probenecid.

In some embodiments, the first layer of the bilayer tablet comprisesabout 500 mg of probenecid.

In some embodiments, the second layer comprises about 500 mg of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof, and the firstlayer comprises about 500 mg of probenecid or the pharmaceuticallyacceptable salt thereof.

In some embodiments, the second layer comprises:

In some embodiments, the second layer comprises Compound III-2.

In some embodiments, the second layer comprises Compound III-2a.

In some embodiments, the second layer comprises Compound III-2b.

In some embodiments, the second layer of the bilayer tablet comprisesabout 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg,about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, orabout 1 g of Compound III-2, Compound III-2a, or Compound III-2b.

In some embodiments, the second layer of the bilayer tablet comprisesabout 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg,about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, orabout 1 g of Compound III-2.

In some embodiments, the second layer of the bilayer tablet comprisesabout 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg,about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, orabout 1 g of Compound III-2a.

In some embodiments, the second layer of the bilayer tablet comprisesabout 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg,about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, orabout 1 g of Compound III-2b.

In some embodiments, the second layer of the bilayer tablet comprisesabout 500 mg of Compound III-2, Compound III-2a, or Compound III-2b.

In some embodiments, the second layer of the bilayer tablet comprisesabout 500 mg of Compound III-2.

In some embodiments, the second layer of the bilayer tablet comprisesabout 500 mg of Compound III-2a.

In some embodiments, the second layer of the bilayer tablet comprisesabout 500 mg of Compound III-2b.

In some embodiments, bilayer tablet further comprises one or more ofpharmaceutical excipients.

In some embodiments, the one or more of pharmaceutical excipients areselected from cellulose, sodium croscamellose, magnesium stearate,lactose monohydrate, and hydroxypropylcellulose.

In some embodiments, the bilayer tablet further comprises about 227±200mg, about 227±150 mg, about 227±100 mg, about 227±90 mg, about 227±80mg, about 227±70 mg, about 227±60 mg, about 227±50 mg, about 227±40 mg,about 227±30 mg, about 227±20 mg, about 227±15 mg, about 227±10 mg, orabout 227±5 mg of microcrystalline cellulose (e.g., about 227 mg ofmicrocrystalline cellulose).

In some embodiments, the bilayer tablet further comprises about 225±200mg, about 225±150 mg, about 225±100 mg, about 225±90 mg, about 225±80mg, about 225±70 mg, about 225±60 mg, about 225±50 mg, about 225±40 mg,about 225±30 mg, about 225±20 mg, about 225±15 mg, about 225±10 mg, orabout 225±5 mg of microcrystalline cellulose (e.g., about 225 mg ofmicrocrystalline cellulose).

In some embodiments, the bilayer tablet further comprises about 56±50mg, about 56±45 mg, about 56±40 mg, about 56±35 mg, about 56±30 mg,about 56±25 mg, about 56±20 mg, about 56±15 mg, about 56±10 mg, about56±5 mg, about 56±4 mg, about 56±3 mg, or about 56±2 mg of sodiumcroscamellose (e.g., about 56 mg of sodium croscamellose).

In some embodiments, the bilayer tablet further comprises about 3.3±3mg, about 3.3±2.5 mg, about 3.3±2 mg, about 3.3±1.8 mg, about 3.3±1.6mg, about 3.3±1.4 mg, about 3.3±1.2 mg, about 3.3±1 mg, about 3.3±0.9mg, about 3.3±0.8 mg, about 3.3±0.7 mg, about 3.3±0.6 mg, about 3.3±0.5mg, about 3.3±0.4 mg, about 3.3±0.3 mg, about 3.3±0.2 mg, or about3.3±0.1 mg of intragranular magnesium stearate (e.g., about 3.3 mg ofintragranular magnesium stearate).

In some embodiments, the bilayer tablet further comprises about 6.9±3mg, about 6.9±2.5 mg, about 6.9±2 mg, about 6.9±1.8 mg, about 6.9±1.6mg, about 6.9±1.4 mg, about 6.9±1.2 mg, about 6.9±1 mg, about 6.9±0.9mg, about 6.9±0.8 mg, about 6.9±0.7 mg, about 6.9±0.6 mg, about 6.9±0.5mg, about 6.9±0.4 mg, about 6.9±0.3 mg, about 6.9±0.2 mg, or about6.9±0.1 mg of extragranular magnesium stearate (e.g., about 6.9 mg ofextragranular magnesium stearate).

In some embodiments, the bilayer tablet further comprises about 70±50mg, about 70±45 mg, about 70±40 mg, about 70±35 mg, about 70±30 mg,about 70±25 mg, about 70±20 mg, about 70±15 mg, about 70±10 mg, about70±5 mg, about 70±4 mg, about 70±3 mg, or about 70±2 mg of lactosemonohydrate 316 (e.g., about 70 mg of lactose monohydrate 316).

In some embodiments, the bilayer tablet further comprises about 69±50mg, about 69±45 mg, about 69±40 mg, about 69±35 mg, about 69±30 mg,about 69±25 mg, about 69±20 mg, about 69±15 mg, about 69±10 mg, about69±5 mg, about 69±4 mg, about 69±3 mg, or about 69±2 mg of lactosemonohydrate 316 (e.g., about 69 mg of lactose monohydrate 316).

In some embodiments, the bilayer tablet further comprises about 21±20mg, about 21±15 mg, about 21±10 mg, about 21±5 mg, about 21±4 mg, about21±3 mg, about 21±2 mg, about 21±1.8 mg, about 21±1.6 mg, about 21±1.4mg, about 21±1.2 mg, about 21±1 mg, about 21±0.9 mg, about 21±0.8 mg,about 21±0.7 mg, about 21±0.6 mg, or about 21±0.5 mg ofhydroxypropylcellulose (e.g., about 21.4 mg of hydroxypropylcellulose).

In some aspects, the present disclosure provides a bilayer tabletcomprising:

a first layer comprising about 500 mg of probenecid; and

a second layer comprising about 500 mg of Compound III-2b.

In some embodiments, the bilayer tablet further comprises:

about 227±200 mg, about 227±150 mg, about 227±100 mg, about 227±90 mg,about 227±80 mg, about 227±70 mg, about 227±60 mg, about 227±50 mg,about 227±40 mg, about 227±30 mg, about 227±20 mg, about 227±15 mg,about 227±10 mg, or about 227±5 mg of microcrystalline cellulose;

about 56±50 mg, about 56±45 mg, about 56±40 mg, about 56±35 mg, about56±30 mg, about 56±25 mg, about 56±20 mg, about 56±15 mg, about 56±10mg, about 56±5 mg, about 56±4 mg, about 56±3 mg, or about 56±2 mg ofsodium croscamellose;

about 3.3±3 mg, about 3.3±2.5 mg, about 3.3±2 mg, about 3.3±1.8 mg,about 3.3±1.6 mg, about 3.3±1.4 mg, about 3.3±1.2 mg, about 3.3±1 mg,about 3.3±0.9 mg, about 3.3±0.8 mg, about 3.3±0.7 mg, about 3.3±0.6 mg,about 3.3±0.5 mg, about 3.3±0.4 mg, about 3.3±0.3 mg, about 3.3±0.2 mg,or about 3.3±0.1 mg of intragranular magnesium stearate;

about 6.9±3 mg, about 6.9±2.5 mg, about 6.9±2 mg, about 6.9±1.8 mg,about 6.9±1.6 mg, about 6.9±1.4 mg, about 6.9±1.2 mg, about 6.9±1 mg,about 6.9±0.9 mg, about 6.9±0.8 mg, about 6.9±0.7 mg, about 6.9±0.6 mg,about 6.9±0.5 mg, about 6.9±0.4 mg, about 6.9±0.3 mg, about 6.9±0.2 mg,or about 6.9±0.1 mg of extragranular magnesium stearate;

about 70±50 mg, about 70±45 mg, about 70±40 mg, about 70±35 mg, about70±30 mg, about 70±25 mg, about 70±20 mg, about 70±15 mg, about 70±10mg, about 70±5 mg, about 70±4 mg, about 70±3 mg, or about 70±2 mg oflactose monohydrate 316; and

about 21±20 mg, about 21±15 mg, about 21±10 mg, about 21±5 mg, about21±4 mg, about 21±3 mg, about 21±2 mg, about 21±1.8 mg, about 21±1.6 mg,about 21±1.4 mg, about 21±1.2 mg, about 21±1 mg, about 21±0.9 mg, about21±0.8 mg, about 21±0.7 mg, about 21±0.6 mg, or about 21±0.5 mg ofhydroxypropylcellulose.

In some embodiments, the bilayer tablet further comprises:

about 225±200 mg, about 225±150 mg, about 225±100 mg, about 225±90 mg,about 225±80 mg, about 225±70 mg, about 225±60 mg, about 225±50 mg,about 225±40 mg, about 225±30 mg, about 225±20 mg, about 225±15 mg,about 225±10 mg, or about 225±5 mg of microcrystalline cellulose;

about 56±50 mg, about 56±45 mg, about 56±40 mg, about 56±35 mg, about56±30 mg, about 56±25 mg, about 56±20 mg, about 56±15 mg, about 56±10mg, about 56±5 mg, about 56±4 mg, about 56±3 mg, or about 56±2 mg ofsodium croscamellose;

about 3.3±3 mg, about 3.3±2.5 mg, about 3.3±2 mg, about 3.3±1.8 mg,about 3.3±1.6 mg, about 3.3±1.4 mg, about 3.3±1.2 mg, about 3.3±1 mg,about 3.3±0.9 mg, about 3.3±0.8 mg, about 3.3±0.7 mg, about 3.3±0.6 mg,about 3.3±0.5 mg, about 3.3±0.4 mg, about 3.3±0.3 mg, about 3.3±0.2 mg,or about 3.3±0.1 mg of intragranular magnesium stearate;

about 6.9±3 mg, about 6.9±2.5 mg, about 6.9±2 mg, about 6.9±1.8 mg,about 6.9±1.6 mg, about 6.9±1.4 mg, about 6.9±1.2 mg, about 6.9±1 mg,about 6.9±0.9 mg, about 6.9±0.8 mg, about 6.9±0.7 mg, about 6.9±0.6 mg,about 6.9±0.5 mg, about 6.9±0.4 mg, about 6.9±0.3 mg, about 6.9±0.2 mg,or about 6.9±0.1 mg of extragranular magnesium stearate;

about 69±50 mg, about 69±45 mg, about 69±40 mg, about 69±35 mg, about69±30 mg, about 69±25 mg, about 69±20 mg, about 69±15 mg, about 69±10mg, about 69±5 mg, about 69±4 mg, about 69±3 mg, or about 69±2 mg oflactose monohydrate 316; and

about 21±20 mg, about 21±15 mg, about 21±10 mg, about 21±5 mg, about21±4 mg, about 21±3 mg, about 21±2 mg, about 21±1.8 mg, about 21±1.6 mg,about 21±1.4 mg, about 21±1.2 mg, about 21±1 mg, about 21±0.9 mg, about21±0.8 mg, about 21±0.7 mg, about 21±0.6 mg, or about 21±0.5 mg ofhydroxypropylcellulose.

In some embodiments, the bilayer tablet further comprises:

from about 220 mg to about 230 mg of microcrystalline cellulose;

from about 50 mg to about 60 mg of sodium croscamellose;

from about 3 mg to about 4 mg of intragranular magnesium stearate;

from about 6 mg to about 8 mg of extragranular magnesium stearate;

from about 65 mg to about 75 mg of lactose monohydrate 316; and

from about 20 to about 23 mg of hydroxypropylcellulose.

In some embodiments, the bilayer tablet further comprises:

about 227 mg of microcrystalline cellulose;

about 56 mg of sodium croscamellose;

about 3.3 mg of intragranular magnesium stearate;

about 6.9 mg of extragranular magnesium stearate;

about 70 mg of lactose monohydrate 316; and

about 21.4 mg of hydroxypropylcellulose.

In some embodiments, the bilayer tablet further comprises:

about 225 mg of microcrystalline cellulose;

about 56 mg of sodium croscamellose;

about 3.3 mg of intragranular magnesium stearate;

about 6.9 mg of extragranular magnesium stearate;

about 69 mg of lactose monohydrate 316; and

about 21.4 mg of hydroxypropylcellulose.

In some embodiments, the bilayer tablet is prepared by a methoddisclosed herein.

In some aspects, the present disclosure provides a bilayer tabletprepared by a method disclosed herein.

Physical Properties of the Bilayer Tablets

In some embodiments, the bilayer tablet is configured to have a whitecolor, a yellow color, a pink color, or any color therebetween.

In some embodiments, the bilayer tablet is configured to have an ovalshape.

In some embodiments, the bilayer tablet is configured to have a lengthof about about 19±10 mm, about 19±9 mm, about 19±8 mm, about 19±7 mm,about 19±6 mm, about 19±5 mm, about 19±4 mm, about 19±3 mm, about 19±2mm, about 19±1 mm, about 19±0.8 mm, about 19±0.6 mm, about 19±0.5 mm,about 19±0.4 mm, about 19±0.3 mm, about 19±0.2 mm, or about 19±0.1 mm(e.g., about 19 mm).

In some embodiments, the bilayer tablet is configured to have a width ofabout 10.3±20 mm, about 10.3±18 mm, about 10.3±16 mm, about 10.3±14 mm,about 10.3±12 mm, about 10.3±10 mm, about 10.3±9 mm, about 10.3±8 mm,about 10.3±7 mm, about 10.3±6 mm, about 10.3±5 mm, about 10.3±4 mm,about 10.3±3 mm, about 10.3±2 mm, about 10.3±1 mm, about 10.3±0.8 mm,about 10.3±0.6 mm, about 10.3±0.5 mm, about 10.3±0.4 mm, about 10.3±0.3mm, about 10.3±0.2 mm, or about 10.3±0.1 mm (e.g., about 10.3 mm).

In some embodiments, the bilayer tablet is configured to have athickness of about 8.2±20 mm, about 8.2±18 mm, about 8.2±16 mm, about8.2±14 mm, about 8.2±12 mm, about 8.2±10 mm, about 8.2±9 mm, about 8.2±8mm, about 8.2±7 mm, about 8.2±6 mm, about 8.2±5 mm, about 8.2±4 mm,about 8.2±3 mm, about 8.2±2 mm, about 8.2±1 mm, about 8.2±0.8 mm, about8.2±0.6 mm, about 8.2±0.5 mm, about 8.2±0.4 mm, about 8.2±0.3 mm, orabout 8.2±0.2 mm.

In some embodiments, the bilayer tablet is configured to have a hardnessof greater than about 80 N, greater than about 85 N, greater than about90 N, greater than about 95 N, greater than about 100 N, greater thanabout 105 N, greater than about 110 N, greater than about 115 N, greaterthan about 120 N, greater than about 125 N, greater than about 130 N,greater than about 140 N, greater than about 150 N, greater than about160 N, greater than about 170 N, greater than about 180 N, greater thanabout 190 N, greater than about 200 N, greater than about 220 N, greaterthan about 240 N, greater than about 260 N, greater than about 270 N,greater than about 280 N, greater than about 290 N, or greater thanabout 300 N.

In some embodiments, the bilayer tablet is configured to have a hardnessof greater than about 120 N.

In some embodiments, the bilayer tablet is configured to have a hardnessof less than 300 N.

In some embodiments, the bilayer tablet is configured to have a hardnessof greater than about 120 N and less than 300 N.

In some embodiments, the bilayer tablet is configured to have afriability of less than about 1%, less than about 0.9%, less than about0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%,less than about 0.4%, less than about 0.3%, less than about 0.2%, orless than about 0.1%.

In some embodiments, the bilayer tablet is configured to have afriability of less than about 0.1%, less than about 0.09%, less thanabout 0.08%, less than about 0.07%, less than about 0.06%, less thanabout 0.05%, less than about 0.04%, less than about 0.03%, less thanabout 0.02%, or less than about 0.01%.

In some embodiments, the bilayer tablet is configured to have a totalvolume of less than 2000 mm³, less than about 1900 mm³, less than about1800 mm³, less than about 1700 mm³, less than about 1600 mm³, less thanabout 1500 mm³, less than about 1400 mm³, less than about 1300 mm³, lessthan about 1250 mm³, less than about 1240 mm³, less than about 1230 mm³,less than about 1220 mm³, less than about 1210 mm³, less than about 1200mm³, less than about 1190 mm³, less than about 1180 mm³, less than about1170 mm³, less than about 1160 mm³, less than about 1150 mm³, less thanabout 1140 mm³, less than about 1130 mm³, less than about 1120 mm³, lessthan about 1110 mm³, less than about 1100 mm³, less than about 1080 mm³,less than about 1060 mm³, less than about 1040 mm³, less than about 1020mm³, or less than about 1010 mm³.

In some embodiments, the bilayer tablet is configured to have a totalvolume of about 1150±300 mm³, about 1150±250 mm³, about 1150±200 mm³,about 1150±180 mm³, about 1150±160 mm³, about 1150±150 mm³, about1150±140 mm³, about 1150±120 mm³, about 1150±100 mm³, about 1150±90 mm³,about 1150±80 mm³, about 1150±70 mm³, about 1150±60 mm³, about 1150±50mm³, about 1150±45 mm³, about 1150±40 mm³, about 1150±35 mm³, about1150±30 mm³, about 1150±25 mm³, about 1150±20 mm³, about 1150±15 mm³,about 1150±10 mm³, about 1150±9 mm³, about 1150±8 mm³, about 1150±7 mm³,about 1150±6 mm³, about 1150±5 mm³, about 1150±4 mm³, mm³, or about1150±3 mm³ (e.g., about 1148 mm³).

In some embodiments, the bilayer tablet is configured to have a totalvolume of about 1050±300 mm³, about 1050±250 mm³, about 1050±200 mm³,about 1050±180 mm³, about 1050±160 mm³, about 1050±150 mm³, about1050±140 mm³, about 1050±120 mm³, about 1050±100 mm³, about 1050±90 mm³,about 1050±80 mm³, about 1050±70 mm³, about 1050±60 mm³, about 1050±50mm³, about 1050±45 mm³, about 1050±40 mm³, about 1050±35 mm³, about1050±30 mm³, about 1050±25 mm³, about 1050±20 mm³, about 1050±15 mm³,about 1050±10 mm³, about 1050±9 mm³, about 1050±8 mm³, about 1050±7 mm³,about 1050±6 mm³, about 1050±5 mm³, about 1050±4 mm³, about 1050±3 mm³,about 1050±2 mm³, or about 1050±1 mm³ (e.g., about 1050 mm³).

In some embodiments, the bilayer tablet is configured to have a porosityof less than about 20%, less than about 15%, less than about 10%, lessthan about 9%, less than about 8%, less than about 7%, less than about6%, less than about 5%, less than about 4%, less than about 3%, lessthan about 2%, less than about 1.8%, less than about 1.6%, less thanabout 1.4%, less than about 1.2%, less than about 1%, less than about0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%,less than about 0.5%, less than about 0.4%, less than about 0.3%, lessthan about 0.2%, or less than about 0.1%.

In some embodiments, the bilayer tablet is configured to have a porosityof about 0.73±0.5%, about 0.73±0.45%, about 0.73±0.4%, about 0.73±0.35%,about 0.73±0.3%, about 0.73±0.25%, about 0.73±0.2%, about 0.73±0.15%,about 0.73±0.1%, about 0.73±0.09%, about 0.73±0.08%, about 0.73±0.07%,about 0.73±0.06%, about 0.73±0.05%, about 0.73±0.04%, about 0.73±0.03%,about 0.73±0.02%, or about 0.73±0.01% (e.g., about 0.73%).

In some embodiments, the bilayer tablet is configured to have a totalpore surface area of less than about 5,000,000 mm², less than about4,000,000 mm², less than about 3,000,000 mm², less than about 2,000,000mm², less than about 1,000,000 mm², less than about 900,000 mm², lessthan about 800,000 mm², less than about 700,000 mm², less than about600,000 mm², less than about 500,000 mm², less than about 400,000 mm²,less than about 300,000 mm², less than about 200,000 mm², less thanabout 100,000 mm², less than about 90,000 mm², less than about 80,000mm², less than about 70,000 mm², less than about 60,000 mm², less thanabout 50,000 mm², less than about 40,000 mm², less than about 30,000mm², less than about 20,000 mm², less than about 10,000 mm², less thanabout 9,000 mm², less than about 8,000 mm², less than about 7,000 mm²,less than about 6,000 mm², less than about 5,000 mm², less than about4900 mm², less than about 4800 mm², less than about 4700 mm², less thanabout 4600 mm², less than about 4500 mm², less than about 4400 mm², lessthan about 4300 mm², less than about 4200 mm², less than about 4100 mm²,less than about 4,000 mm², less than about 3900 mm², less than about3800 mm², less than about 3700 mm², less than about 3600 mm², less thanabout 3500 mm², less than about 3400 mm², less than about 3300 mm², lessthan about 3200 mm², less than about 3100 mm², less than about 3,000mm², less than about 2900 mm², less than about 2800 mm², less than about2700 mm², less than about 2600 mm², less than about 2500 mm², less thanabout 2400 mm², less than about 2300 mm², less than about 2200 mm², lessthan about 2100 mm², less than about 2,000 mm², less than about 1900mm², less than about 1800 mm², less than about 1700 mm², less than about1600 mm², less than about 1500 mm², less than about 1400 mm², less thanabout 1300 mm², less than about 1200 mm², less than about 1100 mm², orless than about 1,000 mm².

In some embodiments, the bilayer tablet is configured to have a totalpore surface area of less than about 3,000 mm².

In some embodiments, the bilayer tablet is configured to have a totalpore surface area of about 2050±1000 mm², about 2050±950 mm², about2050±900 mm², about 2050±850 mm², about 2050±800 mm², about 2050±750mm², about 2050±700 mm², about 2050±650 mm², about 2050±600 mm², about2050±550 mm², about 2050±500 mm², about 2050±450 mm², about 2050±400mm², about 2050±350 mm², about 2050±300 mm², about 2050±250 mm², about2050±200 mm², about 2050±150 mm², about 2050±100 mm², about 2050±90 mm²,about 2050±80 mm², about 2050±70 mm², about 2050±60 mm², about 2050±50mm², about 2050±40 mm², about 2050±30 mm², about 2050±20 mm², about2050±10 mm², or about 2050±5 mm² (e.g., about 2045 mm²).

In some embodiments, the bilayer tablet is configured to have a totalpore count of about 1,000,000 or less, about 900,000 or less, about800,000 or less, about 700,000 or less, about 600,000 or less, about500,000 or less, about 400,000 or less, about 390,000 or less, about380,000 or less, about 370,000 or less, about 360,000 or less, about350,000 or less, about 340,000 or less, about 330,000 or less, about320,000 or less, about 310,000 or less, about 300,000 or less, about290,000 or less, about 280,000 or less, about 270,000 or less, about260,000 or less, about 250,000 or less, about 240,000 or less, about230,000 or less, about 220,000 or less, about 210,000 or less, about200,000 or less, about 190,000 or less, about 180,000 or less, about170,000 or less, about 160,000 or less, about 150,000 or less, about140,000 or less, about 130,000 or less, about 120,000 or less, about110,000 or less, about 100,000 or less, about 90,000 or less, about80,000 or less, about 70,000 or less, about 60,000 or less, about 50,000or less, about 40,000 or less, about 30,000 or less, about 20,000 orless, about 10,000 or less, about 9,000 or less, about 8,000 or less,about 7,000 or less, about 6,000 or less, or about 5,000 or less.

In some embodiments, the bilayer tablet is configured to have a totalpore count of about 255,000±200,000, about 255,000±150,000, about255,000±100,000, about 255,000±90,000, about 255,000±80,000, about255,000±70,000, about 255,000±60,000, about 255,000±50,000, about255,000±40,000, about 255,000±30,000, about 255,000±20,000, or about255,000±10,000.

In some embodiments, the bilayer tablet is configured to have a largestpore volume of about 10 mm³ or less, about 9 mm³ or less, about 8 mm³ orless, about 7 mm³ or less, about 6 mm³ or less, about 5 mm³ or less,about 4 mm³ or less, about 3 mm³ or less, about 2 mm³ or less, about 1.9mm³ or less, about 1.8 mm³ or less, about 1.7 mm³ or less, about 1.6 mm³or less, about 1.5 mm³ or less, about 1.4 mm³ or less, about 1.3 mm³ orless, about 1.2 mm³ or less, about 1.1 mm³ or less, about 1.0 mm³ orless, about 0.95 mm³ or less, about 0.90 mm³ or less, about 0.85 mm³ orless, about 0.80 mm³ or less, about 0.75 mm³ or less, about 0.70 mm³ orless, about 0.65 mm³ or less, about 0.60 mm³ or less, about 0.55 mm³ orless, about 0.50 mm³ or less, about 0.45 mm³ or less, about 0.40 mm³ orless, about 0.35 mm³ or less, about 0.30 mm³ or less, about 0.25 mm³ orless, about 0.20 mm³ or less, about 0.15 mm³ or less, about 0.10 mm³ orless, about 0.09 mm³ or less, about 0.08 mm³ or less, about 0.07 mm³ orless, about 0.06 mm³ or less, about 0.05 mm³ or less, about 0.04 mm³ orless, about 0.03 mm³ or less, about 0.02 mm³ or less, or about 0.01 mm³.

In some embodiments, the bilayer tablet is configured to have a largestpore volume of about 0.84±0.5 mm³, about 0.84±0.45 mm³, about 0.84±0.4mm³, about 0.84±0.35 mm³, about 0.84±0.3 mm³, about 0.84±0.25 mm³, about0.84±0.2 mm³, about 0.84±0.15 mm³, about 0.84±0.1 mm³, about 0.84±0.09mm³, about 0.84±0.08 mm³, about 0.84±0.07 mm³, about 0.84±0.06 mm³,about 0.84±0.05 mm³, about 0.84±0.04 mm³, about 0.84±0.03 mm³, about0.84±0.02 mm³, or about 0.84±0.01 mm³.

In some embodiments, the bilayer tablet is configured to have a ratiobetween the largest pore volume and total pore volume of about 80% orless, about 70% or less, about 60% or less, about 50% or less, about 40%or less, about 30% or less, about 20% or less, about 19% or less, about18% or less, about 17% or less, about 16% or less, about 15% or less,about 14% or less, about 13% or less, about 12% or less, about 11% orless, about 10% or less, about 9% or less, about 8% or less, about 7% orless, about 6% or less, about 5% or less, about 4% or less, about 3% orless, about 2% or less, or about 1% or less.

In some embodiments, the bilayer tablet is configured to have a ratiobetween the largest pore volume and total pore volume of about 10±9%,about 10±8%, about 10±7%, about 10±6%, about 10±5%, about 10±4.5%, about10±4%, about 10±3.5%, about 10±3%, about 10±2.5%, about 10±2%, about10±1.9%, about 10±1.8%, about 10±1.7%, about 10±1.6%, about 10±1.5%,about 10±1.4%, about 10±1.3%, about 10±1.2%, about 10±1.1%, about10±1.0%, about 10±0.9%, about 10±0.8%, about 10±0.7%, about 10±0.6%,about 10±0.5%, about 10±0.4%, about 10±0.3%, about 10±0.2%, or about10±0.1%.

Physicochemical Properties of the Bilayer Tablets

It is understood that the bilayer tablet of the present disclosure mayhave one or more of the physicochemical properties disclosed herein.

In Vitro Release of β-Lactam Compound or the Pharmaceutically AcceptableSalt Thereof

In some embodiments, the bilayer tablet is configured to release about40±20%, about 40±18%, about 40±16%, about 40±14%, about 40±12%, about40±10%, about 40±9%, about 40±8%, about 40±7%, about 40±6%, about 40±5%,about 40±4%, about 40±3%, about 40±2%, or about 40±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about63±20%, about 63±18%, about 63±16%, about 63±14%, about 63±12%, about63±10%, about 63±9%, about 63±8%, about 63±7%, about 63±6%, about 63±5%,about 63±4%, about 63±3%, about 63±2%, or about 63±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about 74±5%,about 74±4%, about 74±3%, about 74±2%, or about 74±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about80±10%, about 80±9%, about 80±8%, about 80±7%, about 80±6%, about 80±5%,about 80±4%, about 80±3%, about 80±2%, or about 80±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 20 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 30 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about91±5%, about 91±4%, about 91±3%, about 91±2%, or about 91±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 45 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 40±20%, about 40±18%, about 40±16%, about 40±14%, about 40±12%,about 40±10%, about 40±9%, about 40±8%, about 40±7%, about 40±6%, about40±5%, about 40±4%, about 40±3%, about 40±2%, or about 40±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes;

about 63±20%, about 63±18%, about 63±16%, about 63±14%, about 63±12%,about 63±10%, about 63±9%, about 63±8%, about 63±7%, about 63±6%, about63±5%, about 63±4%, about 63±3%, about 63±2%, or about 63±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 10 minutes;

about 74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about74±5%, about 74±4%, about 74±3%, about 74±2%, or about 74±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 15 minutes;

about 80±10%, about 80±9%, about 80±8%, about 80±7%, about 80±6%, about80±5%, about 80±4%, about 80±3%, about 80±2%, or about 80±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 20 minutes;

about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% ofthe β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 30 minutes; and

about 91±5%, about 91±4%, about 91±3%, about 91±2%, or about 91±1% ofthe β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 45 minutes.

In some embodiments, the bilayer tablet is configured to release about47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%,about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%, about71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%,about 71±4%, about 71±3%, about 71±2%, or about 71±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about82±10%, about 82±9%, about 82±8%, about 82±7%, about 82±6%, about 82±5%,about 82±4%, about 82±3%, about 82±2%, or about 82±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about 89±5%,about 89±4%, about 89±3%, about 89±2%, or about 89±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 20 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 30 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%,about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes;

about 71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%,about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 10 minutes;

about 82±10%, about 82±9%, about 82±8%, about 82±7%, about 82±6%, about82±5%, about 82±4%, about 82±3%, about 82±2%, or about 82±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 15 minutes;

about 89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about89±5%, about 89±4%, about 89±3%, about 89±2%, or about 89±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 20 minutes; and

about 95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% ofthe β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 30 minutes.

In some embodiments, the bilayer tablet is configured to release about47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%,about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <811>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about70±20%, about 70±18%, about 70±16%, about 70±14%, about 70±12%, about70±10%, about 70±9%, about 70±8%, about 70±7%, about 70±6%, about 70±5%,about 70±4%, about 70±3%, about 70±2%, or about 70±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <811>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about81±10%, about 81±9%, about 81±8%, about 81±7%, about 81±6%, about 81±5%,about 81±4%, about 81±3%, about 81±2%, or about 81±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <811>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%,about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 20 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <811>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 30 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <811>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<811>-compliant test method):

about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%,about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes;

about 70±20%, about 70±18%, about 70±16%, about 70±14%, about 70±12%,about 70±10%, about 70±9%, about 70±8%, about 70±7%, about 70±6%, about70±5%, about 70±4%, about 70±3%, about 70±2%, or about 70±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 10 minutes;

about 81±10%, about 81±9%, about 81±8%, about 81±7%, about 81±6%, about81±5%, about 81±4%, about 81±3%, about 81±2%, or about 81±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 15 minutes;

about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 20 minutes; and

about 93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% ofthe β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 30 minutes.

In some embodiments, the bilayer tablet is configured to release about47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%,about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%, about71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%,about 71±4%, about 71±3%, about 71±2%, or about 71±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about 84±5%,about 84±4%, about 84±3%, about 84±2%, or about 84±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about92±10%, about 92±9%, about 92±8%, about 92±7%, about 92±6%, about 92±5%,about 92±4%, about 92±3%, about 92±2%, or about 92±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 20 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%,about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes;

about 71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%,about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 10 minutes;

about 84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about84±5%, about 84±4%, about 84±3%, about 84±2%, or about 84±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 15 minutes; and

about 92±10%, about 92±9%, about 92±8%, about 92±7%, about 92±6%, about92±5%, about 92±4%, about 92±3%, about 92±2%, or about 92±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 20 minutes.

In some embodiments, the bilayer tablet is configured to release about52±20%, about 52±18%, about 52±16%, about 52±14%, about 52±12%, about52±10%, about 52±9%, about 52±8%, about 52±7%, about 52±6%, about 52±5%,about 52±4%, about 52±3%, about 52±2%, or about 52±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about74±20%, about 74±18%, about 74±16%, about 74±14%, about 74±12%, about74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about 74±5%,about 74±4%, about 74±3%, about 74±2%, or about 74±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about 84±5%,about 84±4%, about 84±3%, about 84±2%, or about 84±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about 89±5%,about 89±4%, about 89±3%, about 89±2%, or about 89±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 20 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 30 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 52±20%, about 52±18%, about 52±16%, about 52±14%, about 52±12%,about 52±10%, about 52±9%, about 52±8%, about 52±7%, about 52±6%, about52±5%, about 52±4%, about 52±3%, about 52±2%, or about 52±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes;

about 74±20%, about 74±18%, about 74±16%, about 74±14%, about 74±12%,about 74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about74±5%, about 74±4%, about 74±3%, about 74±2%, or about 74±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 10 minutes;

about 84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about84±5%, about 84±4%, about 84±3%, about 84±2%, or about 84±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 15 minutes;

about 89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about89±5%, about 89±4%, about 89±3%, about 89±2%, or about 89±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 20 minutes; and

about 95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% ofthe β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 30 minutes.

In some embodiments, the bilayer tablet is configured to release about53±20%, about 53±18%, about 53±16%, about 53±14%, about 53±12%, about53±10%, about 53±9%, about 53±8%, about 53±7%, about 53±6%, about 53±5%,about 53±4%, about 53±3%, about 53±2%, or about 53±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about77±20%, about 77±18%, about 77±16%, about 77±14%, about 77±12%, about77±10%, about 77±9%, about 77±8%, about 77±7%, about 77±6%, about 77±5%,about 77±4%, about 77±3%, about 77±2%, or about 77±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%,about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactamcompound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 20 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about98±2%, about 98±1.8%, about 98±1.6%, about 98±1.4%, about 98±1.2%, about98±1%, about 98±0.9%, about 98±0.8%, about 98±0.7%, about 98±0.6%, about98±0.5%, about 98±0.4%, about 98±0.3%, about 98±0.2%, or about 98±0.1%of the β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 30 minutes as measured in vitro by a testingmethod described herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 53±20%, about 53±18%, about 53±16%, about 53±14%, about 53±12%,about 53±10%, about 53±9%, about 53±8%, about 53±7%, about 53±6%, about53±5%, about 53±4%, about 53±3%, about 53±2%, or about 53±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes;

about 77±20%, about 77±18%, about 77±16%, about 77±14%, about 77±12%,about 77±10%, about 77±9%, about 77±8%, about 77±7%, about 77±6%, about77±5%, about 77±4%, about 77±3%, about 77±2%, or about 77±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 10 minutes;

about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of theβ-lactam compound (e.g., Compound III-2, Compound III-2a, or CompoundIII-2b) or the pharmaceutically acceptable salt thereof in the bilayertablet within about 15 minutes;

about 93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% ofthe β-lactam compound (e.g., Compound III-2, Compound III-2a, orCompound III-2b) or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 20 minutes; and

about 98±2%, about 98±1.8%, about 98±1.6%, about 98±1.4%, about 98±1.2%,about 98±1%, about 98±0.9%, about 98±0.8%, about 98±0.7%, about 98±0.6%,about 98±0.5%, about 98±0.4%, about 98±0.3%, about 98±0.2%, or about98±0.1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a,or Compound III-2b) or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 30 minutes.

In Vitro Release of Probenecid or the Pharmaceutically Acceptable SaltThereof

In some embodiments, the bilayer tablet is configured to release about25±20%, about 25±18%, about 25±16%, about 25±14%, about 25±12%, about25±10%, about 25±9%, about 25±8%, about 25±7%, about 25±6%, about 25±5%,about 25±4%, about 25±3%, about 25±2%, or about 25±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about66±20%, about 66±18%, about 66±16%, about 66±14%, about 66±12%, about66±10%, about 66±9%, about 66±8%, about 66±7%, about 66±6%, about 66±5%,about 66±4%, about 66±3%, about 66±2%, or about 66±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about92±20%, about 92±18%, about 92±16%, about 92±14%, about 92±12%, about92±10%, about 92±9%, about 92±8%, about 92±7%, about 92±6%, about 92±5%,about 92±4%, about 92±3%, about 92±2%, or about 92±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 25±10%, about 25±9%, about 25±8%, about 25±7%, about 25±6%, about25±5%, about 25±4%, about 25±3%, about 25±2%, or about 25±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 5 minutes;

about 66±10%, about 66±9%, about 66±8%, about 66±7%, about 66±6%, about66±5%, about 66±4%, about 66±3%, about 66±2%, or about 66±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 10 minutes; and

about 92±2%, about 92±1.8%, about 92±1.6%, about 92±1.4%, about 92±1.2%,about 92±1%, about 92±0.9%, about 92±0.8%, about 92±0.7%, about 92±0.6%,about 92±0.5%, about 92±0.4%, about 92±0.3%, about 92±0.2%, or about92±0.1% of probenecid or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 15 minutes.

In some embodiments, the bilayer tablet is configured to release about28±20%, about 28±18%, about 28±16%, about 28±14%, about 28±12%, about28±10%, about 28±9%, about 28±8%, about 28±7%, about 28±6%, about 28±5%,about 28±4%, about 28±3%, about 28±2%, or about 28±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%, about71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%,about 71±4%, about 71±3%, about 71±2%, or about 71±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about94±20%, about 94±18%, about 94±16%, about 94±14%, about 94±12%, about94±10%, about 94±9%, about 94±8%, about 94±7%, about 94±6%, about 94±5%,about 94±4%, about 94±3%, about 94±2%, or about 94±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 28±10%, about 28±9%, about 28±8%, about 28±7%, about 28±6%, about28±5%, about 28±4%, about 28±3%, about 28±2%, or about 28±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 5 minutes;

about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 10 minutes; and

about 94±2%, about 94±1.8%, about 94±1.6%, about 94±1.4%, about 94±1.2%,about 94±1%, about 94±0.9%, about 94±0.8%, about 94±0.7%, about 94±0.6%,about 94±0.5%, about 94±0.4%, about 94±0.3%, about 94±0.2%, or about94±0.1% of probenecid or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 15 minutes.

In some embodiments, the bilayer tablet is configured to release about30±20%, about 30±18%, about 30±16%, about 30±14%, about 30±12%, about30±10%, about 30±9%, about 30±8%, about 30±7%, about 30±6%, about 30±5%,about 30±4%, about 30±3%, about 30±2%, or about 30±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about72±20%, about 72±18%, about 72±16%, about 72±14%, about 72±12%, about72±10%, about 72±9%, about 72±8%, about 72±7%, about 72±6%, about 72±5%,about 72±4%, about 72±3%, about 72±2%, or about 72±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about94±20%, about 94±18%, about 94±16%, about 94±14%, about 94±12%, about94±10%, about 94±9%, about 94±8%, about 94±7%, about 94±6%, about 94±5%,about 94±4%, about 94±3%, about 94±2%, or about 94±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 30±10%, about 30±9%, about 30±8%, about 30±7%, about 30±6%, about30±5%, about 30±4%, about 30±3%, about 30±2%, or about 30±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 5 minutes;

about 72±10%, about 72±9%, about 72±8%, about 72±7%, about 72±6%, about72±5%, about 72±4%, about 72±3%, about 72±2%, or about 72±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 10 minutes; and

about 94±2%, about 94±1.8%, about 94±1.6%, about 94±1.4%, about 94±1.2%,about 94±1%, about 94±0.9%, about 94±0.8%, about 94±0.7%, about 94±0.6%,about 94±0.5%, about 94±0.4%, about 94±0.3%, about 94±0.2%, or about94±0.1% of probenecid or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 15 minutes.

In some embodiments, the bilayer tablet is configured to release about41±20%, about 41±18%, about 41±16%, about 41±14%, about 41±12%, about41±10%, about 41±9%, about 41±8%, about 41±7%, about 41±6%, about 41±5%,about 41±4%, about 41±3%, about 41±2%, or about 41±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about87±20%, about 87±18%, about 87±16%, about 87±14%, about 87±12%, about87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%,about 87±4%, about 87±3%, about 87±2%, or about 87±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about96±20%, about 96±18%, about 96±16%, about 96±14%, about 96±12%, about96±10%, about 96±9%, about 96±8%, about 96±7%, about 96±6%, about 96±5%,about 96±4%, about 96±3%, about 96±2%, or about 96±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 41±10%, about 41±9%, about 41±8%, about 41±7%, about 41±6%, about41±5%, about 41±4%, about 41±3%, about 41±2%, or about 41±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 5 minutes;

about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 10 minutes; and

about 96±2%, about 96±1.8%, about 96±1.6%, about 96±1.4%, about 96±1.2%,about 96±1%, about 96±0.9%, about 96±0.8%, about 96±0.7%, about 96±0.6%,about 96±0.5%, about 96±0.4%, about 96±0.3%, about 96±0.2%, or about96±0.1% of probenecid or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 15 minutes.

In some embodiments, the bilayer tablet is configured to release about43±20%, about 43±18%, about 43±16%, about 43±14%, about 43±12%, about43±10%, about 43±9%, about 43±8%, about 43±7%, about 43±6%, about 43±5%,about 43±4%, about 43±3%, about 43±2%, or about 43±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about86±20%, about 86±18%, about 86±16%, about 86±14%, about 86±12%, about86±10%, about 86±9%, about 86±8%, about 86±7%, about 86±6%, about 86±5%,about 86±4%, about 86±3%, about 86±2%, or about 86±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about98±20%, about 98±18%, about 98±16%, about 98±14%, about 98±12%, about98±10%, about 98±9%, about 98±8%, about 98±7%, about 98±6%, about 98±5%,about 98±4%, about 98±3%, about 98±2%, or about 98±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 15 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method):

about 43±10%, about 43±9%, about 43±8%, about 43±7%, about 43±6%, about43±5%, about 43±4%, about 43±3%, about 43±2%, or about 43±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 5 minutes;

about 86±10%, about 86±9%, about 86±8%, about 86±7%, about 86±6%, about86±5%, about 86±4%, about 86±3%, about 86±2%, or about 86±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 10 minutes; and

about 98±2%, about 98±1.8%, about 98±1.6%, about 98±1.4%, about 98±1.2%,about 98±1%, about 98±0.9%, about 98±0.8%, about 98±0.7%, about 98±0.6%,about 98±0.5%, about 98±0.4%, about 98±0.3%, about 98±0.2%, or about98±0.1% of probenecid or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 15 minutes.

In some embodiments, the bilayer tablet is configured to release about75±20%, about 75±18%, about 75±16%, about 75±14%, about 75±12%, about75±10%, about 75±9%, about 75±8%, about 75±7%, about 75±6%, about 75±5%,about 75±4%, about 75±3%, about 75±2%, or about 75±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release about37±20%, about 37±18%, about 37±16%, about 37±14%, about 37±12%, about37±10%, about 37±9%, about 37±8%, about 37±7%, about 37±6%, about 37±5%,about 37±4%, about 37±3%, about 37±2%, or about 37±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes as measured in vitro by a testing methoddescribed herein (e.g., the USP <711>-compliant test method).

In some embodiments, the bilayer tablet is configured to release, asmeasured in vitro by a testing method described herein (e.g., the USP<711>-compliant test method): about 37±10%, about 37±9%, about 37±8%,about 37±7%, about 37±6%, about 37±5%, about 37±4%, about 37±3%, about37±2%, or about 37±1% of probenecid or the pharmaceutically acceptablesalt thereof in the bilayer tablet within about 5 minutes;

about 75±10%, about 75±9%, about 75±8%, about 75±7%, about 75±6%, about75±5%, about 75±4%, about 75±3%, about 75±2%, or about 75±1% ofprobenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 10 minutes; and

about 96±2%, about 96±1.8%, about 96±1.6%, about 96±1.4%, about 96±1.2%,about 96±1%, about 96±0.9%, about 96±0.8%, about 96±0.7%, about 96±0.6%,about 96±0.5%, about 96±0.4%, about 96±0.3%, about 96±0.2%, or about96±0.1% of probenecid or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 15 minutes.

Testing Methods for Physicochemical Properties of Bilayer Tablets

It is understood that the physicochemical properties (e.g., in vitrorelease characteristics of the bilayer tablet may be measured in vitroby using methods common in the art, e.g., the USP<711>-compliant testingmethod.

In some embodiments, the USP <711>-compliant method is carried out witha paddle apparatus, a basket apparatus, a reciprocating cylinder, or aflow-through cell as described in the method.

In some embodiments, the USP <711>-compliant method is carried out witha paddle apparatus as described in the method.

In some embodiments, the USP <711>-compliant method is carried out witha temperature of about 37±10° C., about 37±8° C., about 37±6° C., about37±5° C., about 37±4° C., about 37±3° C., about 37±2° C., about 37±1°C., or about 37±0.5° C. In some embodiments, the method is the USP<711>-compliant method is carried out with a temperature at about 37° C.

In some embodiments, the USP <711>-compliant method is carried out witha sampling volume of about 2.5±2 mL, about 2.5±1.8 mL, about 2.5±1.6 mL,about 2.5±1.4 mL, about 2.5±1.2 mL, about 2.5±1 mL, about 2.5±0.9 mL,about 2.5±0.8 mL, about 2.5±0.7 mL, about 2.5±0.6 mL, about 2.5±0.5 mL,about 2.5±0.4 mL, about 2.5±0.3 mL, about 2.5±0.2 mL, or about 2.5±0.1mL. In some embodiments, the USP <711>-compliant method is carried outwith a sampling volume of about 2.5 mL.

In some embodiments, the USP <711>-compliant method is carried out witha rotation speed of about 75±50 rpm, about 75±40 rpm, about 75±30 rpm,about 75±20 rpm, about 75±15 rpm, about 75±10 rpm, or about 75±5 rpm. Insome embodiments, the USP <711>-compliant method is carried out with arotation speed of about 75 rpm.

In some embodiments, the USP <711>-compliant method is carried out witha media volume of about 900±500 mL, about 900±450 mL, about 900±400 mL,about 900±350 mL, about 900±300 mL, about 900±250 mL, about 900±200 mL,about 900±150 mL, about 900±100 mL, about 900±90 mL, about 900±80 mL,about 900±70 mL, about 900±60 mL, about 900±50 mL, about 900±40 mL,about 900±30 mL, about 900±20 mL, or about 900±10 mL. In someembodiments, the USP <711>-compliant method is carried out with a mediavolume of about 900 mL.

In some embodiments, the USP <711>-compliant method is carried out witha pH value of about 6.8±3, about 6.8±2.8, about 6.8±2.6, about 6.8±2.4,about 6.8±2.2, about 6.8±2, about 6.8±1.8, about 6.8±1.6, about 6.8±1.4,about 6.8±1.2, about 6.8±1, about 6.8±0.9, about 6.8±0.8, about 6.8±0.7,about 6.8±0.6, about 6.8±0.5, about 6.8±0.4, about 6.8±0.3, about6.8±0.2, or about 6.8±0.1. In some embodiments, the USP <711>-compliantmethod is carried out with a pH value of about 6.8.

In some embodiments, the USP <711>-compliant method is carried out withanalysis by HPLC (e.g., HPLC-UV).

β-Lactam Compounds

In some embodiments, the β-lactam compound is a monobactam or a prodrugthereof.

In some embodiments, the β-lactam compound is aztreonam, tigemonam,carumonam, nocardicin A, a prodrug thereof, an analog thereof, or aderivative thereof.

In some embodiments, the β-lactam compound is a penem, a carbapenem, aclavam, or a prodrug thereof.

In some embodiments, the β-lactam compound is benzylpenicillin,benzathine benzylpenicillin, procaine benzylpenicillin,phenoxymethylpenicillin, propicillin, pheneticillin, azidocillin,clometocillin, penamecillin, cloxacillin (e.g., dicloxacillin orflucloxacillin), oxacillin, nafcillin, methicillin, amoxicillin,ampicillin (e.g., pivampicillin, hetacillin, bacampicillin,metampicillin, talampicillin), epicillin, ticarcillin, carbenicillin,carindacillin, temocillin, piperacillin, azlocillin, mezlocillin,mecillinam (e.g., pivmecillinam), sulbenicillin, a pharmaceuticallyacceptable salt thereof, a prodrug thereof, an analog thereof, or aderivative thereof.

In some embodiments, the β-lactam compound is a penem, a carbapenem, ora prodrug thereof.

In some embodiments, the β-lactam compound is a thiopenem, an oxypenem,an aminopenem, an alkylpenems, an arylpenem, or a prodrug thereof.

In some embodiments, the β-lactam compound is ertapenem, anantipseudomonal carbapenem (e.g., doripenem, imipenem, meropenem),biapenem, panipenem, sulopenem, tebipenem, faropenem, a pharmaceuticallyacceptable salt thereof, a prodrug thereof, an analog thereof, or aderivative thereof.

In some embodiments, the β-lactam compound is a cephem, a carbacephem,an oxacephem, or a prodrug thereof.

In some embodiments, the β-lactam compound is cefazolin, cefalexin,cefadroxil, cefapirin, cefazedone, cefazaflur, cefradine, cefroxadine,ceftezole, cefaloglycin, cefacetrile, cefalonium, cefaloridine,cefalotin, cefatrizine, cefaclor, cefotetan, cephamycin (e.g.,cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefamandole,cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuzonam,cefmetazole), carbacephem (e.g., loracarbef), cefixime, ceftriaxone,antipseudomonal (e.g, ceftazidime, cefoperazone), cefdinir, cefcapene,cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide,cefpodoxime, ceftibuten, cefditoren, cefetamet, cefodizime, cefpimizole,cefsulodin, cefteram, ceftiolene, oxacephem (e.g., flomoxef, latamoxef),cefepime, cefozopran, cefpirome, cefquinome, ceftaroline fosamil,ceftolozane, ceftobiprole, ceftiofur, cefquinome, cefovecin, apharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof.

In some embodiments, the β-lactam compound is a thiopenem or a prodrugthereof.

In some embodiments, the β-lactam compound is of Formula (I):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof, wherein R¹ is H or optionallysubstituted alkyl.

In some embodiments, the β-lactam compound is of Formula (Ia):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof.

In some embodiments, the β-lactam compound is of Formula (Ib):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof.

In some embodiments, R¹ is H.

In some embodiments, the β-lactam compound is of Formula (II):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof.

In some embodiments, the β-lactam compound is of Formula (IIa):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof.

In some embodiments, the β-lactam compound is of Formula (IIb):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof.

In some embodiments, R¹ is optionally substituted alkyl.

In some embodiments, the β-lactam compound is of any one of Formulae(III), (IIIa), and (IIIb):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof, wherein R² is H or optionallysubstituted alkyl.

In some embodiments, the β-lactam compound is selected from the groupconsisting of:

pharmaceutically acceptable salts thereof, prodrugs thereof, analogsthereof, and derivatives thereof.

In some embodiments, the 3β-lactam compound is selected from the groupconsisting of:

pharmaceutically acceptable salts thereof, prodrugs thereof, analogsthereof, and derivatives thereof.

In some embodiments, the β-lactam compound is selected from

pharmaceutically acceptable salts thereof, prodrugs thereof, analogsthereof, and derivatives thereof.

Compounds of the present disclosure that contain nitrogens In someembodiments, the β-lactam compound is of any one of Formulae (IV),(IVa), and (IVb):

a pharmaceutically acceptable salt thereof, a prodrug thereof, an analogthereof, or a derivative thereof, wherein R³ is H or optionallysubstituted alkyl.

In some embodiments, R³ is C₂-C₈ alkyl.

In some embodiments, R³ is CH₂CH₃, CH₂CH₂CH₃, or CH₂CH(CH₃)₂.

Methods of Preparation

In some aspects, the present disclosure provides a method of preparing abilayer tablet.

In some embodiments, the bilayer tablet of the present disclosure isprepared by a method disclosed herein.

In some embodiments, the method comprises:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force, therebyforming a pre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force, thereby forming a pre-coated bilayertablet.

In some embodiments, the first granular material is prepared by aprocess disclosed herein (e.g., the process as described in FIG. 1). Insome embodiments, the first granular material is prepared by granulatinga mixture of powdery or solid probenecid or the pharmaceuticallyacceptable salt thereof and one or more excipients.

In some embodiments, the second granular material is prepared by aprocess disclosed herein (e.g., the process as described in FIG. 2).

In some embodiments, the second granular material is prepared bygranulating a mixture of powdery or solid β-lactam compound or thepharmaceutically acceptable salt thereof (e.g., Compound III-2b) and oneor more excipients.

In some embodiments, the granulated mixture is further compacted (e.g.,by one or more roller compactions), thereby forming a compacted ribbonsection.

In some embodiments, the compacted ribbon section is further granulated,crushed, and/or screened through one or more suitable size screens.

In some embodiments, the compaction step and the granulation, crushing,and/or screening step are repeated for one or more times.

In some embodiments, the first force is about 20 kN or less, about 19 kNor less, about 18 kN or less, about 17 kN or less, about 16 kN or less,about 15 kN or less, about 14.5 kN or less, about 14 kN or less, about13.5 kN or less, about 13 kN or less, about 12.5 kN or less, about 12 kNor less, about 11.5 kN or less, about 11 kN or less, about 10.5 kN orless, about 10 kN or less, about 9.5 kN or less, about 9 kN or less,about 8.5 kN or less, about 8 kN or less, about 7.5 kN or less, about 7kN or less, about 6.5 kN or less, about 6 kN or less, about 5.5 kN orless, about 5 kN or less, about 4.5 kN or less, about 4 kN or less,about 3.5 kN or less, about 3 kN or less, about 2.5 kN or less, about 2kN or less, about 1.5 kN or less, about 1 kN or less, or about 0.5 kN orless.

In some embodiments, the first force is about 11.5 kN or less.

In some embodiments, the second force is about 50 kN or less, about 45kN or less, about 40 kN or less, about 39 kN or less, about 38 kN orless, about 37 kN or less, about 36 kN or less, about 35 kN or less,about 34 kN or less, about 33 kN or less, about 32 kN or less, about 31kN or less, about 30 kN or less, about 29 kN or less, about 28 kN orless, about 27 kN or less, about 26 kN or less, about 25 kN or less,about 20 kN or less, about 15 kN or less, about 10 kN or less, about 9kN or less, about 8 kN or less, about 7 kN or less, about 6 kN or less,about 5 kN or less, about 4 kN or less, about 3 kN or less, about 2 kNor less, about 1 kN or less.

In some embodiments, the second force is about 30 kN or less.

In some embodiments, the first force is about 11.5 kN or less, and thesecond force is about 30 kN or less.

In some embodiments, the method comprises:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force being about20 kN or less, about 19 kN or less, about 18 kN or less, about 17 kN orless, about 16 kN or less, about 15 kN or less, about 14.5 kN or less,about 14 kN or less, about 13.5 kN or less, about 13 kN or less, about12.5 kN or less, about 12 kN or less, about 11.5 kN or less, about 11 kNor less, about 10.5 kN or less, about 10 kN or less, about 9.5 kN orless, about 9 kN or less, about 8.5 kN or less, about 8 kN or less,about 7.5 kN or less, about 7 kN or less, about 6.5 kN or less, about 6kN or less, about 5.5 kN or less, about 5 kN or less, about 4.5 kN orless, about 4 kN or less, about 3.5 kN or less, about 3 kN or less,about 2.5 kN or less, about 2 kN or less, about 1.5 kN or less, or about1 kN or less, thereby forming a pre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force being about 50 kN or less, about 45 kN orless, about 40 kN or less, about 39 kN or less, about 38 kN or less,about 37 kN or less, about 36 kN or less, about 35 kN or less, about 34kN or less, about 33 kN or less, about 32 kN or less, about 31 kN orless, about 30 kN or less, about 29 kN or less, about 28 kN or less,about 27 kN or less, about 26 kN or less, about 25 kN or less, about 20kN or less, about 15 kN or less, about 10 kN or less, about 9 kN orless, about 8 kN or less, about 7 kN or less, about 6 kN or less, about5 kN or less, about 4 kN or less, about 3 kN or less, about 2 kN orless, about 1 kN or less, thereby forming a pre-coated bilayer tablet.

In some embodiments, the method comprises:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force being about11.5 kN or less, thereby forming a pre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force being about 30 kN or less, thereby forminga pre-coated bilayer tablet.

In some embodiments, the first force is about 1.5±1.2 kN, about 1.5±1.1kN, about 1.5±1.0 kN, about 1.5±0.9 kN, about 1.5±0.8 kN, about 1.5±0.75kN, about 1.5±0.7 kN, about 1.5±0.65 kN, about 1.5±0.6 kN, about1.5±0.55 kN, about 1.5±0.5 kN, about 1.5±0.45 kN, about 1.5±0.4 kN,about 1.5±0.35 kN, about 1.5±0.3 kN, about 1.5±0.25 kN, about 1.5±0.2kN, about 1.5±0.15 kN, about 1.5±0.1 kN, or about 1.5±0.05 kN.

In some embodiments, the first force is about 1.5 kN.

In some embodiments, the first force is about 0.5±0.45 kN, about 0.5±0.4kN, about 0.5±0.35 kN, about 0.5±0.3 kN, about 0.5±0.25 kN, about0.5±0.2 kN, about 0.5±0.15 kN, about 0.5±0.1 kN, or about 0.5±0.05 kN.

In some embodiments, the first force is about 0.5 kN.

In some embodiments, the second force is about 11.5±10 kN, about 11.5±9kN, about 11.5±8 kN, about 11.5±7 kN, about 11.5±6 kN, about 11.5±5 kN,about 11.5±4 kN, about 11.5±3 kN, about 11.5±2 kN, about 11.5±1 kN,about 11.5±0.9 kN, about 11.5±0.8 kN, about 11.5±0.7 kN, about 11.5±0.6kN, about 11.5±0.5 kN, about 11.5±0.4 kN, about 11.5±0.3 kN, about11.5±0.2 kN, or about 11.5±0.1 kN.

In some embodiments, the second force is about 11.5 kN.

In some embodiments, the first force is about 1.5 kN, and the secondforce is about 30 kN.

In some embodiments, the method comprises:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force being about1.5±1.2 kN, about 1.5±1.1 kN, about 1.5±1.0 kN, about 1.5±0.9 kN, about1.5±0.8 kN, about 1.5±0.75 kN, about 1.5±0.7 kN, about 1.5±0.65 kN,about 1.5±0.6 kN, about 1.5±0.55 kN, about 1.5±0.5 kN, about 1.5±0.45kN, about 1.5±0.4 kN, about 1.5±0.35 kN, about 1.5±0.3 kN, about1.5±0.25 kN, about 1.5±0.2 kN, about 1.5±0.15 kN, about 1.5±0.1 kN, orabout 1.5±0.05 kN, thereby forming a pre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force being about 11.5±10 kN, about 11.5±9 kN,about 11.5±8 kN, about 11.5±7 kN, about 11.5±6 kN, about 11.5±5 kN,about 11.5±4 kN, about 11.5±3 kN, about 11.5±2 kN, about 11.5±1 kN,about 11.5±0.9 kN, about 11.5±0.8 kN, about 11.5±0.7 kN, about 11.5±0.6kN, about 11.5±0.5 kN, about 11.5±0.4 kN, about 11.5±0.3 kN, about11.5±0.2 kN, or about 11.5±0.1 kN, thereby forming a pre-coated bilayertablet.

In some embodiments, the method comprises:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force being about1.5 kN, thereby forming a pre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force being about 11.5 kN, thereby forming apre-coated bilayer tablet.

In some embodiments, the first force is about 1.25±1.2 kN, about1.25±1.1 kN, about 1.25±1.0 kN, about 1.25±0.9 kN, about 1.25±0.8 kN,about 1.25±0.75 kN, about 1.25±0.7 kN, about 1.25±0.65 kN, about1.25±0.6 kN, about 1.25±0.55 kN, about 1.25±0.5 kN, about 1.25±0.45 kN,about 1.25±0.4 kN, about 1.25±0.35 kN, about 1.25±0.3 kN, about1.25±0.25 kN, about 1.25±0.2 kN, about 1.25±0.15 kN, about 1.25±0.1 kN,or about 1.25±0.05 kN.

In some embodiments, the first force is about 1.25 kN.

In some embodiments, the second force is about 30±20 kN, about 30±15 kN,about 30±10 kN, about 30±9 kN, about 30±8 kN, about 30±7 kN, about 30±6kN, about 30±5 kN, about 30±4 kN, about 30±3 kN, about 30±2 kN, about30±1 kN, about 30±0.9 kN, about 30±0.8 kN, about 30±0.7 kN, about 30±0.6kN, about 30±0.5 kN, about 30±0.4 kN, about 30±0.3 kN, about 30±0.2 kN,or about 30±0.1 kN.

In some embodiments, the second force is about 30 kN.

In some embodiments, the first force is about 1.25 kN, and the secondforce is about 30 kN.

In some embodiments, the method comprises:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force being about1.25±1.2 kN, about 1.25±1.1 kN, about 1.25±1.0 kN, about 1.25±0.9 kN,about 1.25±0.8 kN, about 1.25±0.75 kN, about 1.25±0.7 kN, about1.25±0.65 kN, about 1.25±0.6 kN, about 1.25±0.55 kN, about 1.25±0.5 kN,about 1.25±0.45 kN, about 1.25±0.4 kN, about 1.25±0.35 kN, about1.25±0.3 kN, about 1.25±0.25 kN, about 1.25±0.2 kN, about 1.25±0.15 kN,about 1.25±0.1 kN, or about 1.25±0.05 kN, thereby forming apre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force being about 30±20 kN, about 30±15 kN, about30±10 kN, about 30±9 kN, about 30±8 kN, about 30±7 kN, about 30±6 kN,about 30±5 kN, about 30±4 kN, about 30±3 kN, about 30±2 kN, about 30±1kN, about 30±0.9 kN, about 30±0.8 kN, about 30±0.7 kN, about 30±0.6 kN,about 30±0.5 kN, about 30±0.4 kN, about 30±0.3 kN, about 30±0.2 kN, orabout 30±0.1 kN, thereby forming a pre-coated bilayer tablet.

In some embodiments, the method comprises:

i) compressing a first granular material comprising probenecid or apharmaceutically acceptable salt thereof with a first force being about1.25 kN, thereby forming a pre-compressed first layer;

ii) adding a second granular material comprising a β-lactam compound ora pharmaceutically acceptable salt thereof to the pre-compressed firstlayer;

iii) compressing the pre-compressed first layer and the second granularmaterial with a second force being about 30 kN, thereby forming apre-coated bilayer tablet.

In some embodiments, the method further comprises:

iv) coating the pre-coated bilayer tablet with a coating agent, therebyforming the bilayer tablet.

In some embodiments, the coating agent comprises polyvinyl alcohol(PVA).

In some embodiments, the coating agent is free of polyethelyne glycol(PEG) or soy lecithin.

In some embodiments, the coating agent is Opadry® AMB White 80W68912.

In some embodiments, the coating agent is Opadry AMB Pink 80W240026

Methods of Use

In some aspects, the present disclosure provides a method of treating orpreventing a disease, comprising administering to a subject in needthereof a pharmaceutically effective amount of a bilayer tabletdisclosed herein.

In some aspects, the present disclosure provides a bilayer tabletdisclosed herein for use in treating or preventing a disease in asubject in need thereof.

Treated Subjects and Diseases

In some embodiments, the subject in need thereof is an animal. In someembodiments, the subject in need thereof is a human.

In some embodiments, the subject in need thereof is a human of 18 yearsor older.

In some embodiments, the subject in need thereof is a human younger than18 years.

In some embodiments, the disease is associated with an increased ordecreased population of one or more microorganisms (e.g., bacteria) inthe subject.

In some embodiments, the disease is associated with an increasedpopulation of one or more microorganisms (e.g., bacteria) in thesubject. In some embodiments, the method of the present disclosureresults in a decrease population of the one or more microorganisms(e.g., bacteria) in the subject.

In some embodiments, the disease is associated with a decreasedpopulation of one or more microorganisms (e.g., bacteria) in thesubject. In some embodiments, the method of the present disclosureresults in an increased population of the one or more microorganisms(e.g., bacteria) in the subject.

In some embodiments, the disease is associated with an increased ordecreased population of one or more bacteria selected from Escherichiacoli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae,Klebsiella oxytoca, Citrobacter freundii complex, Clostridiumclostridioforme, Eubacterium lentum, Peptostreptococcus species,Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroidescoprocola, Prevotella copri, Porphyromonas asaccharolytica, andPrevotella bivia or any organisms in the following genera:Succinivibrio, Alistipes, Prevotella, Paraprevotella, Parabacteroides,and Odoribacter.

In some embodiments, the disease is associated with an increased ordecreased population of one or more bacteria selected fromStaphylococcus epidermidis, Streptococcus pneumonia, Staphylococcusaureus, Streptococcus agalactiae, and Streptococcus pyogenes.

In some embodiments, the disease is associated with an increased ordecreased population of one or more bacteria selected from Citrobacterfreundii, Citrobacter koseri, Enterobacter aerogenes, Enterobactercloacae, Haemophilus influenza, Haemophilus parainfluenzae, Klebsiellaoxytoca, Moraxella catarrhalis, Morganella morganii, Proteus vulgaris,Providencia rettgeri, Providencia stuartii, and Serratia marcescens.

In some embodiments, the disease is associated with an increased ordecreased population of one or more bacteria selected from Bacteroidesvulgatus, Clostridium perfringens, and Fusobacterium spp.

In some embodiments, the disease is associated with an infection. Insome embodiments, the infection is a gram-negative infection. In someembodiments, the infection is a gram-positive infection.

In some embodiments, the infection is resistant to one or moreantibiotics when being administered without probenecid or thepharmaceutically acceptable salt thereof.

In some embodiments, the infection is resistant to one or more β-lactamcompounds when being administered without probenecid or thepharmaceutically acceptable salt thereof.

In some embodiments, the disease is an uncomplicated urinary tractinfection, a complicated urinary tract infection, a complicatedintra-abdominal infection, an uncomplicated intra-abdominal infection,pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvicinflammatory disease, prostatitis, bone infection, joint infection,diabetic foot infection and infectious diarrhea.

In some embodiments, the disease is associated with (e.g., resultedfrom) the alteration of the microbiome in the subject.

In some embodiments, the disease is associated with (e.g., resultedfrom) the alteration of the microbiome in the human subject.

In some embodiments, the disease is a neurodegenerative disease.

In some embodiments, the disease is amyotrophic lateral sclerosis,Parkinson's disease, Alzheimer's disease, schizophrenia or Huntington'sdisease.

In some embodiments, the disease is Alzheimer's disease. It is notedthat probenecid has been found to increase the concentrations ofβ-lactam compounds in the cerebrospinal fluid (Ralph G. Dacey and MerleA. Sande, Antimicrobial Agents and Chemotherapy 6:437-441 (1974)). Morerecently, a bacterial pathogen, Porphyromonas gingivalis, has been foundin brain in association with pathologic lesions, which are associatedwith Alzheimer's disease (Dominy et al., Sci. Adv. 5:eaau3333 (2019),and sulopenem is active against this bacterium (Lois M. Ednie and PeterC. Appelbaum, Antimicrobial Agents and Chemotherapy 53: 2163-2170(2009)). Without wishing to be bound by theory, it is understood thatthe beta-lactam compounds (e.g., Compound III-2b), when being dosed withprobenecid, may lead to more effective treatment of a brain infectionwith this organism relative to treatment with sulopenem alone.

In some embodiments, the disease is cancer.

In some embodiments, the cancer is a solid cancer, e.g., ovarian cancer,breast cancer, head and neck cancer, renal cancer, bladder cancer,hepatocellular cancer, colorectal cancer, or lymphoma, or anycombination thereof.

In some embodiments, the cancer is sarcoma or carcinoma, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,prostate cancer, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, hepatoma, bile ductcarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,cervical cancer, testicular tumor, lung carcinoma, small cell lungcarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma.

In some embodiments, the cancer is leukemia, e.g., acute lymphocyticleukemia and acute myelocytic leukemia (myeloblastic, promyelocytic,myelomonocytic, monocytic and erythroleukemia); or chronic leukemia(chronic myelocytic (granulocytic) leukemia and chronic lymphocyticleukemia).

In some embodiments, the cancer is polycythemia vera, lymphoma(Hodgkin's disease and non-Hodgkin's disease), multiple myeloma,Waldenström's macroglobulinemia, or heavy chain disease.

In some embodiments, the disease is an inflammatory bowel disease.

In some embodiments, the inflammatory bowel disease is Crohn's disease,ulcerative colitis, indeterminate colitis, irritable bowel syndrome,microscopic colitis, diversion colitis, or Behcet's disease.

Administrations

In some embodiments, the bilayer tablet is administered once daily.

In some embodiments, the bilayer tablet is administered twice daily.

In some embodiments, the bilayer tablet is administered three or moretimes daily.

In some embodiments, the bilayer tablet is administered for about 1 day.

In some embodiments, the bilayer tablet is administered for more thanabout 1 day.

In some embodiments, the bilayer tablet for about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 14 days,or about 30 days.

In some embodiments, the bilayer tablet is administered with one or moredrug holidays.

In some embodiments, the bilayer tablet is administered without any drugholiday.

In some embodiments, the bilayer tablet is administered to the subjectwith food (e.g., the subject is fed).

In some embodiments, the subject is fed within about 1 hour, about 2hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours,about 2 days, about 5 days, or about 10 days prior to administration ofthe bilayer tablet.

In some embodiments, the subject in need thereof is fasted for about 1hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about24 hours, about 2 days, about 5 days, or about 10 days prior toadministration of the bilayer tablet.

In some embodiments, the subject in need thereof is fed within about 1hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about24 hours, about 2 days, about 5 days, or about 10 days afteradministration of the bilayer tablet.

In some embodiments, the subject in need thereof is fasted for about 1hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about24 hours, about 2 days, about 5 days, or about 10 days afteradministration of the bilayer tablet.

Effects on the AUC and/or C_(max)

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having an area under the curve(AUC) that is higher in the subject in need thereof as compared to acomparable subject being administered with a comparable composition.

In some embodiments, the administration results in a maximum plasmaconcentration (C_(max)) in the subject in need thereof thatsubstantially the same as compared to a comparable subject beingadministered with a comparable composition.

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) that is higher in the subject in needthereof as compared to a comparable subject being administered with acomparable composition by about 5% or greater, about 10% or greater,about 15% or greater, about 20% or greater, about 25% or greater, about30% or greater, about 40% or greater, about 50% or greater, about 60% orgreater, about 80% or greater, about 100% or greater, about 150% orgreater, about 200% or greater, about 300% or greater, about 400% orgreater, or about 500% or greater within about 30 minutes, about 1 hour,about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, or about 7 days from the administration.

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) that is higher in the subject in needthereof as compared to a comparable subject being administered with acomparable composition by about 5% or greater, about 10% or greater,about 15% or greater, about 20% or greater, about 25% or greater, about30% or greater, about 40% or greater, about 50% or greater, about 60% orgreater, about 80% or greater, about 100% or greater, about 150% orgreater, about 200% or greater, about 300% or greater, about 400% orgreater, or about 500% or greater within about 30 minutes, about 1 hour,about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, or about 7 days from the administration; and

a maximum plasma concentration (C_(max)) in the subject in need thereofthat is from about 50% to about 150%, from about 60% to about 140%, fromabout 70% to about 130%, from about 80% to about 120%, from about 90% toabout 110%, from about 95% to about 105%, or from 98% to about 102% ascompared to a comparable subject being administered with a comparablecomposition.

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) that is higher in the subject in needthereof as compared to a comparable subject being administered with acomparable composition by about 5% or greater, about 10% or greater,about 15% or greater, about 20% or greater, about 25% or greater, about30% or greater, about 40% or greater, about 50% or greater, about 60% orgreater, about 80% or greater, about 100% or greater, about 150% orgreater, about 200% or greater, about 300% or greater, about 400% orgreater, or about 500% or greater within about 30 minutes, about 1 hour,about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, or about 7 days from the administration; and

a maximum plasma concentration (C_(max)) in the subject in need thereofthat is substantially the same as compared to a comparable subject beingadministered with a comparable composition.

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) that is higher in the subject in needthereof as compared to a comparable subject being administered with thebilayer tablet without food (e.g., the comparable subject is fasted) byabout 5% or greater, about 10% or greater, about 15% or greater, about20% or greater, about 25% or greater, about 30% or greater, about 40% orgreater, about 50% or greater, about 60% or greater, about 80% orgreater, about 100% or greater, about 150% or greater, about 200% orgreater, about 300% or greater, about 400% or greater, or about 500% orgreater within about 30 minutes, about 1 hour, about 2 hours, about 3hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about7 days from the administration.

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) that is higher in the subject in needthereof as compared to a comparable subject being administered with thebilayer tablet without food (e.g., the comparable subject is fasted) byabout 5% or greater, about 10% or greater, about 15% or greater, about20% or greater, about 25% or greater, about 30% or greater, about 40% orgreater, about 50% or greater, about 60% or greater, about 80% orgreater, about 100% or greater, about 150% or greater, about 200% orgreater, about 300% or greater, about 400% or greater, or about 500% orgreater within about 30 minutes, about 1 hour, about 2 hours, about 3hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about7 days from the administration; and

a maximum plasma concentration (C_(max)) in the subject in need thereofthat is from about 50% to about 150%, from about 60% to about 140%, fromabout 70% to about 130%, from about 80% to about 120%, from about 90% toabout 110%, from about 95% to about 105%, or from 98% to about 102% ascompared to a comparable subject being administered with the bilayertablet without food (e.g., the comparable subject is fasted).

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) that is higher in the subject in needthereof as compared to a comparable subject being administered with thebilayer tablet without food (e.g., the comparable subject is fasted) byabout 5% or greater, about 10% or greater, about 15% or greater, about20% or greater, about 25% or greater, about 30% or greater, about 40% orgreater, about 50% or greater, about 60% or greater, about 80% orgreater, about 100% or greater, about 150% or greater, about 200% orgreater, about 300% or greater, about 400% or greater, or about 500% orgreater within about 30 minutes, about 1 hour, about 2 hours, about 3hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about7 days from the administration; and

a maximum plasma concentration (C_(max)) in the subject in need thereofthat is substantially the same as compared to a comparable subject beingadministered with the bilayer tablet without food (e.g., the comparablesubject is fasted).

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) being from about 4325±3000 ng·h/mL, about4325±2500 ng·h/mL, about 4325±2000 ng·h/mL, about 4325±1500 ng·h/mL,about 4325±1000 ng·h/mL, about 4325±900 ng·h/mL, about 4325±800 ng·h/mL,about 4325±700 ng·h/mL, about 4325±600 ng·h/mL, about 4325±500 ng·h/mL,about 4325±400 ng·h/mL, about 4325±300 ng·h/mL, about 4325±200 ng·h/mL,about 4325±100 ng·h/mL, about 4325±90 ng·h/mL, about 4325±80 ng·h/mL,about 4325±70 ng·h/mL, about 4325±60 ng·h/mL, about 4325±50 ng·h/mL,about 4325±40 ng·h/mL, about 4325±30 ng·h/mL, about 4325±20 ng·h/mL, orabout 4325±10 ng·h/mL (e.g., about 4325 ng·h/mL) within about 1 day fromthe administration.

In some embodiments, the bilayer tablet is administered to the subjectin need thereof with food (e.g., the subject is fed), and theadministration results in a plasma concentration for the β-lactamcompound having:

an area under the curve (AUC) being from about 6600±3000 ng·h/mL, about6600±2500 ng·h/mL, about 6600±2000 ng·h/mL, about 6600±1500 ng·h/mL,about 6600±1000 ng·h/mL, about 6600±900 ng·h/mL, about 6600±800 ng·h/mL,about 6600±700 ng·h/mL, about 6600±600 ng·h/mL, about 6600±500 ng·h/mL,about 6600±400 ng·h/mL, about 6600±300 ng·h/mL, about 6600±200 ng·h/mL,about 6600±100 ng·h/mL, about 6600±90 ng·h/mL, about 6600±80 ng·h/mL,about 6600±70 ng·h/mL, about 6600±60 ng·h/mL, about 6600±50 ng·h/mL,about 6600±40 ng·h/mL, about 6600±30 ng·h/mL, about 6600±20 ng·h/mL, orabout 6600±10 ng·h/mL (e.g., about 6600 ng·h/mL) within about 1 day fromthe administration.

In some embodiments, the administration results in a plasmaconcentration for the β-lactam compound having:

an area under the curve (AUC) being from about 5100±3000 ng·h/mL, about5100±2500 ng·h/mL, about 5100±2000 ng·h/mL, about 5100±1500 ng·h/mL,about 5100±1000 ng·h/mL, about 5100±900 ng·h/mL, about 5100±800 ng·h/mL,about 5100±700 ng·h/mL, about 5100±600 ng·h/mL, about 5100±500 ng·h/mL,about 5100±400 ng·h/mL, about 5100±300 ng·h/mL, about 5100±200 ng·h/mL,about 5100±100 ng·h/mL, about 5100±90 ng·h/mL, about 5100±80 ng·h/mL,about 5100±70 ng·h/mL, about 5100±60 ng·h/mL, about 5100±50 ng·h/mL,about 5100±40 ng·h/mL, about 5100±30 ng·h/mL, about 5100±20 ng·h/mL, orabout 5100±10 ng·h/mL (e.g., about 5100 ng·h/mL) within about 1 day fromthe administration.

In some embodiments, the bilayer tablet is administered to the subjectin need thereof with food (e.g., the subject is fed), and theadministration results in a plasma concentration for the β-lactamcompound having:

an area under the curve (AUC) being from about 7340±3000 ng·h/mL, about7340±2500 ng·h/mL, about 7340±2000 ng·h/mL, about 7340±1500 ng·h/mL,about 7340±1000 ng·h/mL, about 7340±900 ng·h/mL, about 7340±800 ng·h/mL,about 7340±700 ng·h/mL, about 7340±600 ng·h/mL, about 7340±500 ng·h/mL,about 7340±400 ng·h/mL, about 7340±300 ng·h/mL, about 7340±200 ng·h/mL,about 7340±100 ng·h/mL, about 7340±90 ng·h/mL, about 7340±80 ng·h/mL,about 7340±70 ng·h/mL, about 7340±60 ng·h/mL, about 7340±50 ng·h/mL,about 7340±40 ng·h/mL, about 7340±30 ng·h/mL, about 7340±20 ng·h/mL, orabout 7340±10 ng·h/mL (e.g., about 7340 ng·h/mL) within about 1 day fromthe administration.

Definitions

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain(linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆alkyl is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl groups.Examples of alkyl include, moieties having from one to six carbon atoms,such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl. In certain embodiments,a straight chain or branched alkyl has six or fewer carbon atoms (e.g.,C₁-C₆ for straight chain, C₃-C₆ for branched chain), and in anotherembodiment, a straight chain or branched alkyl has four or fewer carbonatoms.

As used herein, the term “cycloalkyl” refers to a saturated orunsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused,bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g.,C₃-C₁₂, C₃-C₁₀, or C₃-C₈). Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,1,2,3,4-tetrahydronaphthalenyl, and adamantyl.

As used herein, the term “heterocycloalkyl” refers to a saturated orunsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic(fused, bridged, or spiro rings), or 11-14 membered tricyclic ringsystem (fused, bridged, or spiro rings) having one or more heteroatoms(such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independentlyselected from the group consisting of nitrogen, oxygen and sulfur,unless specified otherwise. Examples of heterocycloalkyl groups include,but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl,dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl,azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl,tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl,tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl,1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl,1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl,3′H-spiro[cyclohexane-1,1′-isobenzofuran]-yl,7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-yl,3′H-spiro[cyclohexane-1,1′-furo[3,4-c]pyridin]-yl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl,1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl,3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl,4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl,2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl,2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl,2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl,2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclicnon-aromatic rings, only one of the rings needs to be non-aromatic(e.g., 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydroindole).

As used herein, the term “optionally substituted alkyl” refers tounsubstituted alkyl or alkyl having designated substituents replacingone or more hydrogen atoms on one or more carbons of the hydrocarbonbackbone. Such substituents can include, for example, alkyl, alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

As used herein, the term “alkyl linker” or “alkylene linker” is intendedto include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain (linear) saturateddivalent aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆ branchedsaturated aliphatic hydrocarbon groups. For example, C₁-C₆ alkylenelinker is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkylene linkergroups. Examples of alkylene linker include, moieties having from one tosix carbon atoms, such as, but not limited to, methyl (—CH₂—), ethyl(—CH₂CH₂—), n-propyl (—CH₂CH₂CH₂—), i-propyl (—CHCH₃CH₂—), n-butyl(—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl (—C(CH₃) 2CH₂—),n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl (—CHCH₃CH₂CH₂CH₂—) or n-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₂—).

As used herein, the term “alkenyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double bond. For example, the term“alkenyl” includes straight chain alkenyl groups (e.g., ethenyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl,decenyl), and branched alkenyl groups. In certain embodiments, astraight chain or branched alkenyl group has six or fewer carbon atomsin its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branchedchain). The term “C₂-C₆” includes alkenyl groups containing two to sixcarbon atoms. The term “C₃-C₆” includes alkenyl groups containing threeto six carbon atoms.

As used herein, the term “optionally substituted alkenyl” refers tounsubstituted alkenyl or alkenyl having designated substituentsreplacing one or more hydrogen atoms on one or more hydrocarbon backbonecarbon atoms. Such substituents can include, for example, alkyl,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic orheteroaromatic moiety.

As used herein, the term “alkynyl” includes unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but which contain at least one triple bond. For example,“alkynyl” includes straight chain alkynyl groups (e.g., ethynyl,propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl,decynyl), and branched alkynyl groups. In certain embodiments, astraight chain or branched alkynyl group has six or fewer carbon atomsin its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branchedchain). The term “C₂-C₆” includes alkynyl groups containing two to sixcarbon atoms. The term “C₃-C₆” includes alkynyl groups containing threeto six carbon atoms. As used herein, “C₂-C₆ alkenylene linker” or “C₂-C₆alkynylene linker” is intended to include C₂, C₃, C₄, C₅ or C₆ chain(linear or branched) divalent unsaturated aliphatic hydrocarbon groups.For example, C₂-C₆ alkenylene linker is intended to include C₂, C₃, C₄,C₅ and C₆ alkenylene linker groups.

As used herein, the term “optionally substituted alkynyl” refers tounsubstituted alkynyl or alkynyl having designated substituentsreplacing one or more hydrogen atoms on one or more hydrocarbon backbonecarbon atoms. Such substituents can include, for example, alkyl,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substitutedcycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both theunsubstituted moieties and the moieties having one or more of thedesignated substituents. For example, substituted heterocycloalkylincludes those substituted with one or more alkyl groups, such as2,2,6,6-tetramethyl-piperidinyl and2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

As used herein, the term “aryl” includes groups with aromaticity,including “conjugated,” or multicyclic systems with one or more aromaticrings and do not contain any heteroatom in the ring structure. Examplesinclude phenyl, naphthalenyl, etc.

As used herein, the term “heteroaryl” is intended to include a stable5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-memberedbicyclic aromatic heterocyclic ring which consists of carbon atoms andone or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independentlyselected from the group consisting of nitrogen, oxygen and sulfur. Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR whereinR is H or other substituents, as defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), wherep=1 or 2). It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1. Examples of heteroaryl groupsinclude pyrrole, furan, thiophene, thiazole, isothiazole, imidazole,triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine,pyridazine, pyrimidine, and the like.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryland heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, quinoline, isoquinoline, naphthrydine, indole,benzofuran, purine, benzofuran, deazapurine, indolizine.

The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can besubstituted at one or more ring positions (e.g., the ring-forming carbonor heteroatom such as N) with such substituents as described above, forexample, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (includingalkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroarylgroups can also be fused or bridged with alicyclic or heterocyclicrings, which are not aromatic so as to form a multicyclic system (e.g.,tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).

As used herein, the term “carbocycle” or “carbocyclic ring” is intendedto include any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. Carbocycle includes cycloalkyl and aryl. For example, aC₃-C₁₄ carbocycle is intended to include a monocyclic, bicyclic ortricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbonatoms. Examples of carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl,indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are alsoincluded in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, and [4.4.0] bicyclodecaneand [2.2.2] bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro ringsare also included.

As used herein, the term “heterocycle” or “heterocyclic group” includesany ring structure (saturated, unsaturated, or aromatic) which containsat least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, Oand S). Heterocycle includes heterocycloalkyl and heteroaryl. Examplesof heterocycles include, but are not limited to, morpholine,pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane,pyran, tetrahydropyran, azetidine, and tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g.,benzo[d][1,3]dioxole-5-yl), morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

As used herein, the term “substituted,” means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is oxo or keto (i.e., ═O), then 2 hydrogen atoms onthe atom are replaced. Keto substituents are not present on aromaticmoieties. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituentor formula for a compound, its definition at each occurrence isindependent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R moieties, thenthe group may optionally be substituted with up to two R moieties and Rat each occurrence is selected independently from the definition of R.Also, combinations of substituents and/or variables are permissible, butonly if such combinations result in stable compounds.

As used herein, the term “hydroxy” or “hydroxyl” includes groups with an—OH or —O⁻.

As used herein, the term “halo” or “halogen” refers to fluoro, chloro,bromo and iodo. The term “perhalogenated” generally refers to a moietywherein all hydrogen atoms are replaced by halogen atoms. The term“haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substitutedwith one or more halogen atoms.

As used herein, the term “carbonyl” includes compounds and moietieswhich contain a carbon connected with a double bond to an oxygen atom.Examples of moieties containing a carbonyl include, but are not limitedto, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,etc.

As used herein, the term “carboxyl” refers to —COOH or its C₁-C₆ alkylester.

As used herein, the term “acyl” includes moieties that contain the acylradical (R—C(O)—) or a carbonyl group. As used herein, the term“substituted acyl” includes acyl groups where one or more of thehydrogen atoms are replaced by, for example, alkyl groups, alkynylgroups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

As used herein, the term “aroyl” includes moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy, etc.

As used herein, the term “alkoxyalkyl,” “alkylaminoalkyl,” and“thioalkoxyalkyl” include alkyl groups, as described above, whereinoxygen, nitrogen, or sulfur atoms replace one or more hydrocarbonbackbone carbon atoms.

As used herein, the term “alkoxy” or “alkoxyl” includes substituted andunsubstituted alkyl, alkenyl and alkynyl groups covalently linked to anoxygen atom. Examples of alkoxy groups or alkoxyl radicals include, butare not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy andpentoxy groups. Examples of substituted alkoxy groups includehalogenated alkoxy groups. The alkoxy groups can be substituted withgroups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

As used herein, the term “ether” or “alkoxy” includes compounds ormoieties which contain an oxygen bonded to two carbon atoms orheteroatoms. For example, the term includes “alkoxyalkyl,” which refersto an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygenatom which is covalently bonded to an alkyl group.

As used herein, the term “ester” includes compounds or moieties whichcontain a carbon or a heteroatom bound to an oxygen atom which is bondedto the carbon of a carbonyl group. The term “ester” includesalkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.

As used herein, the term “thioalkyl” includes compounds or moietieswhich contain an alkyl group connected with a sulfur atom. The thioalkylgroups can be substituted with groups such as alkyl, alkenyl, alkynyl,halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (includingalkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties.

As used herein, the term “thiocarbonyl” or “thiocarboxy” includescompounds and moieties which contain a carbon connected with a doublebond to a sulfur atom.

As used herein, the term “thioether” includes moieties which contain asulfur atom bonded to two carbon atoms or heteroatoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includemoieties with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” refers to moieties wherein an alkyl, alkenyl oralkynyl group is bonded to a sulfur atom which is covalently bonded toan alkenyl group; and alkthioalkynyls” refers to moieties wherein analkyl, alkenyl or alkynyl group is bonded to a sulfur atom which iscovalently bonded to an alkynyl group.

As used herein, the term “amine” or “amino” refers to —NH₂. “Alkylamino”includes groups of compounds wherein the nitrogen of —NH₂ is bound to atleast one alkyl group. Examples of alkylamino groups includebenzylamino, methylamino, ethylamino, phenethylamino, etc.

As used herein, the term “dialkylamino” includes groups wherein thenitrogen of —NH₂ is bound to two alkyl groups. Examples of dialkylaminogroups include, but are not limited to, dimethylamino and diethylamino.

As used herein, the terms “arylamino” and “diarylamino” include groupswherein the nitrogen is bound to at least one or two aryl groups,respectively.

As used herein, the terms “aminoaryl” and “aminoaryloxy” refer to aryland aryloxy substituted with amino.

As used herein, the terms “alkylarylamino,” “alkylaminoaryl” or“arylaminoalkyl” refers to an amino group which is bound to at least onealkyl group and at least one aryl group.

As used herein, the terms “alkaminoalkyl” refers to an alkyl, alkenyl,or alkynyl group bound to a nitrogen atom which is also bound to analkyl group.

As used herein, the terms “acylamino” includes groups wherein nitrogenis bound to an acyl group. Examples of acylamino include, but are notlimited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureidogroups.

As used herein, the term“amide” or “aminocarboxy” includes compounds ormoieties that contain a nitrogen atom that is bound to the carbon of acarbonyl or a thiocarbonyl group.

As used herein, the term “alkaminocarboxy” includes alkyl, alkenyl oralkynyl groups bound to an amino group which is bound to the carbon of acarbonyl or thiocarbonyl group.

As used herein, the term“arylaminocarboxy” includes aryl or heteroarylmoieties bound to an amino group that is bound to the carbon of acarbonyl or thiocarbonyl group.

As used herein, the terms “alkylaminocarboxy”, “alkenylaminocarboxy”,“alkynylaminocarboxy” and “arylaminocarboxy” include moieties whereinalkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to anitrogen atom which is in turn bound to the carbon of a carbonyl group.

Amides can be substituted with substituents such as straight chainalkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle.Substituents on amide groups may be further substituted.

It is understood that probenecid (e.g., sold under the brandnameProbalan) is of the following structure:

Compounds of the present disclosure that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to affordother compounds of the present disclosure. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the presentdisclosure can be converted to N-hydroxy or N-alkoxy compounds. Forexample, N-hydroxy compounds can be prepared by oxidation of the parentamine by an oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent disclosure includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like, it being understood that not all isomers mayhave the same level of activity. In addition, a crystal polymorphism maybe present for the compounds represented by the formula. It is notedthat any crystal form, crystal form mixture, or anhydride or hydratethereof is included in the scope of the present disclosure.

As used herein, the term “isomerism” means compounds that have identicalmolecular formulae but differ in the sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereoisomers,” and stereoisomers that are non-superimposable mirrorimages of each other are termed “enantiomers” or sometimes opticalisomers. A mixture containing equal amounts of individual enantiomericforms of opposite chirality is termed a “racemic mixture.”

As used herein, the term “chiral center” refers to a carbon atom bondedto four nonidentical substituents.

As used herein, the term “chiral isomer” means a compound with at leastone chiral center. Compounds with more than one chiral center may existeither as an individual diastereomer or as a mixture of diastereomers,termed “diastereomeric mixture.” When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

As used herein, the term “geometric isomer” means the diastereomers thatowe their existence to hindered rotation about double bonds or acycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

It is to be understood that the compounds of the present disclosure maybe depicted as different chiral isomers or geometric isomers. It is alsoto be understood that when compounds have chiral isomeric or geometricisomeric forms, all isomeric forms are intended to be included in thescope of the present disclosure, and the naming of the compounds doesnot exclude any isomeric forms, it being understood that not all isomersmay have the same level of activity.

It is to be understood that the structures and other compounds discussedin this disclosure include all atropic isomers thereof. It is also to beunderstood that not all atropic isomers may have the same level ofactivity.

As used herein, the term “atropic isomers” are a type of stereoisomer inwhich the atoms of two isomers are arranged differently in space.Atropic isomers owe their existence to a restricted rotation caused byhindrance of rotation of large groups about a central bond. Such atropicisomers typically exist as a mixture, however as a result of recentadvances in chromatography techniques, it has been possible to separatemixtures of two atropic isomers in select cases.

As used herein, the term “tautomer” is one of two or more structuralisomers that exist in equilibrium and is readily converted from oneisomeric form to another. This conversion results in the formalmigration of a hydrogen atom accompanied by a switch of adjacentconjugated double bonds. Tautomers exist as a mixture of a tautomericset in solution. In solutions where tautomerization is possible, achemical equilibrium of the tautomers will be reached. The exact ratioof the tautomers depends on several factors, including temperature,solvent and pH. The concept of tautomers that are interconvertible bytautomerizations is called tautomerism. Of the various types oftautomerism that are possible, two are commonly observed. In keto-enoltautomerism a simultaneous shift of electrons and a hydrogen atomoccurs. Ring-chain tautomerism arises as a result of the aldehyde group(—CHO) in a sugar chain molecule reacting with one of the hydroxy groups(—OH) in the same molecule to give it a cyclic (ring-shaped) form asexhibited by glucose.

It is to be understood that the compounds of the present disclosure maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present disclosure, and the naming ofthe compounds does not exclude any tautomer form. It will be understoodthat certain tautomers may have a higher level of activity than others.

As used herein, the term “crystal polymorphs”, “polymorphs” or “crystalforms” means crystal structures in which a compound (or a salt orsolvate thereof) can crystallize in different crystal packingarrangements, all of which have the same elemental composition.Different crystal forms usually have different X-ray diffractionpatterns, infrared spectral, melting points, density hardness, crystalshape, optical and electrical properties, stability and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Crystalpolymorphs of the compounds can be prepared by crystallization underdifferent conditions.

It is to be understood that the compounds of any Formula describedherein include the compounds themselves, as well as their salts, andtheir solvates, if applicable. A salt, for example, can be formedbetween an anion and a positively charged group (e.g., amino) on asubstituted benzene compound. Suitable anions include chloride, bromide,iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate,methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate,malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate,lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

As used herein, the term “pharmaceutically acceptable anion” refers toan anion suitable for forming a pharmaceutically acceptable salt.Likewise, a salt can also be formed between a cation and a negativelycharged group (e.g., carboxylate) on a substituted benzene compound.Suitable cations include sodium ion, potassium ion, magnesium ion,calcium ion, and an ammonium cation such as tetramethylammonium ion. Thesubstituted benzene compounds also include those salts containingquaternary nitrogen atoms.

It is to be understood that the compounds of the present disclosure, forexample, the salts of the compounds, can exist in either hydrated orunhydrated (the anhydrous) form or as solvates with other solventmolecules. Nonlimiting examples of hydrates include monohydrates,dihydrates, etc. Nonlimiting examples of solvates include ethanolsolvates, acetone solvates, etc.

As used herein, the term “solvate” means solvent addition forms thatcontain either stoichiometric or non-stoichiometric amounts of solvent.Some compounds have a tendency to trap a fixed molar ratio of solventmolecules in the crystalline solid state, thus forming a solvate. If thesolvent is water the solvate formed is a hydrate; and if the solvent isalcohol, the solvate formed is an alcoholate. Hydrates are formed by thecombination of one or more molecules of water with one molecule of thesubstance in which the water retains its molecular state as H₂O.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

As used herein, the term “derivative” refers to compounds that have acommon core structure, and are substituted with various groups asdescribed herein.

As used herein, the term “bioisostere” refers to a compound resultingfrom the exchange of an atom or of a group of atoms with another,broadly similar, atom or group of atoms. The objective of a bioisostericreplacement is to create a new compound with similar biologicalproperties to the parent compound. The bioisosteric replacement may bephysicochemically or topologically based. Examples of carboxylic acidbioisosteres include, but are not limited to, acyl sulfonimides,tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie,Chem. Rev. 96, 3147-3176, 1996.

It is to be understood that the present disclosure is intended toinclude all isotopes of atoms occurring in the present compounds.Isotopes include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude C-13 and C-14.

As used herein, the expressions “one or more of A, B, or C,” “one ormore A, B, or C,” “one or more of A, B, and C,” “one or more A, B, andC,” “selected from the group consisting of A, B, and C”, “selected fromA, B, and C”, and the like are used interchangeably and all refer to aselection from a group consisting of A, B, and/or C, i.e., one or moreAs, one or more Bs, one or more Cs, or any combination thereof, unlessindicated otherwise.

It is to be understood that the present disclosure provides methods forthe synthesis of the compounds of any of the Formulae described herein.The present disclosure also provides detailed methods for the synthesisof various disclosed compounds of the present disclosure according tothe following schemes as well as those shown in the Examples.

It is to be understood that, throughout the description, wherecompositions are described as having, including, or comprising specificcomponents, it is contemplated that compositions also consistessentially of, or consist of, the recited components. Similarly, wheremethods or processes are described as having, including, or comprisingspecific process steps, the processes also consist essentially of, orconsist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions is immaterial so long as the invention remains operable.Moreover, two or more steps or actions can be conducted simultaneously.

It is to be understood that the synthetic processes of the disclosurecan tolerate a wide variety of functional groups, therefore varioussubstituted starting materials can be used. The processes generallyprovide the desired final compound at or near the end of the overallprocess, although it may be desirable in certain instances to furtherconvert the compound to a pharmaceutically acceptable salt thereof.

It is to be understood that compounds of the present disclosure can beprepared in a variety of ways using commercially available startingmaterials, compounds known in the literature, or from readily preparedintermediates, by employing standard synthetic methods and procedureseither known to those skilled in the art, or which will be apparent tothe skilled artisan in light of the teachings herein. Standard syntheticmethods and procedures for the preparation of organic molecules andfunctional group transformations and manipulations can be obtained fromthe relevant scientific literature or from standard textbooks in thefield. Although not limited to any one or several sources, classic textssuch as Smith, M. B., March, J., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 5^(th) edition, John Wiley & Sons:New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups inOrganic Synthesis, 3^(rd) edition, John Wiley & Sons: New York, 1999; R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L.Fieser and M. Fieser, Fieser and Fieser's Reagents for OrganicSynthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), incorporated by reference herein, are useful and recognizedreference textbooks of organic synthesis known to those in the art

One of ordinary skill in the art will note that, during the reactionsequences and synthetic schemes described herein, the order of certainsteps may be changed, such as the introduction and removal of protectinggroups. One of ordinary skill in the art will recognize that certaingroups may require protection from the reaction conditions via the useof protecting groups. Protecting groups may also be used todifferentiate similar functional groups in molecules. A list ofprotecting groups and how to introduce and remove these groups can befound in Greene, T. W., Wuts, P. G. M., Protective Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons: New York, 1999.

It is to be understood that, unless otherwise stated, any description ofa method of treatment includes use of the compounds to provide suchtreatment or prophylaxis as is described herein, as well as use of thecompounds to prepare a medicament to treat or prevent such condition.The treatment includes treatment of human or non-human animals includingrodents and other disease models.

As used herein, the term “subject” is interchangeable with the term“subject in need thereof”, both of which refer to a subject having adisease or having an increased risk of developing the disease. A“subject” includes a mammal. The mammal can be e.g., a human orappropriate non-human mammal, such as primate, mouse, rat, dog, cat,cow, horse, goat, camel, sheep or a pig. The subject can also be a birdor fowl. In one embodiment, the mammal is a human.

As used herein, the term “candidate compound” refers to a compound ofthe present disclosure, or a pharmaceutically acceptable salt, polymorphor solvate thereof, that has been or will be tested in one or more invitro or in vivo biological assays, in order to determine if thatcompound is likely to elicit a desired biological or medical response ina cell, tissue, system, animal or human that is being sought by aresearcher or clinician. A candidate compound is a compound of thepresent disclosure, or a pharmaceutically acceptable salt, polymorph orsolvate thereof. The biological response or effect can occur in vitro orin an animal model, as well as other biological changes that areobservable in vitro. In vitro or in vivo biological assays can include,but are not limited to, enzymatic activity assays, electrophoreticmobility shift assays, reporter gene assays, in vitro cell viabilityassays, and the assays described herein.

As used herein, the term “treating” or “treat” describes the managementand care of a patient for the purpose of combating a disease, condition,or disorder and includes the administration of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, polymorph or solvatethereof, to alleviate the symptoms or complications of a disease,condition or disorder, or to eliminate the disease, condition ordisorder. The term “treat” can also include treatment of a cell in vitroor an animal model.

As used herein, the term “temporal proximity” refers to thatadministration of one therapeutic agent (e.g., a β-lactam compounddisclosed herein) occurs within a time period before or after theadministration of another therapeutic agent (e.g., probenecid), suchthat the therapeutic effect of the one therapeutic agent overlaps withthe therapeutic effect of the other therapeutic agent. In someembodiments, the therapeutic effect of the one therapeutic agentcompletely overlaps with the therapeutic effect of the other therapeuticagent. In some embodiments, “temporal proximity” means thatadministration of one therapeutic agent occurs within a time periodbefore or after the administration of another therapeutic agent, suchthat there is a synergistic effect between the one therapeutic agent andthe other therapeutic agent. “Temporal proximity” may vary according tovarious factors, including but not limited to, the age, gender, weight,genetic background, medical condition, disease history, and treatmenthistory of the subject to which the therapeutic agents are to beadministered; the disease or condition to be treated or ameliorated; thetherapeutic outcome to be achieved; the dosage, dosing frequency, anddosing duration of the therapeutic agents; the pharmacokinetics andpharmacodynamics of the therapeutic agents; and the route(s) throughwhich the therapeutic agents are administered. In some embodiments,“temporal proximity” means within 15 minutes, within 30 minutes, withinan hour, within two hours, within four hours, within six hours, withineight hours, within 12 hours, within 18 hours, within 24 hours, within36 hours, within 2 days, within 3 days, within 4 days, within 5 days,within 6 days, within a week, within 2 weeks, within 3 weeks, within 4weeks, with 6 weeks, or within 8 weeks. In some embodiments, multipleadministration of one therapeutic agent can occur in temporal proximityto a single administration of another therapeutic agent. In someembodiments, temporal proximity may change during a treatment cycle orwithin a dosing regimen.

It is to be understood that a compound of the present disclosure, or apharmaceutically acceptable salt, polymorph or solvate thereof, can ormay also be used to prevent a relevant disease, condition or disorder,or used to identify suitable candidates for such purposes.

As used herein, the term “preventing,” “prevent,” or “protectingagainst” describes reducing or eliminating the onset of the symptoms orcomplications of such disease, condition or disorder.

It is to be understood that one skilled in the art may refer to generalreference texts for detailed descriptions of known techniques discussedherein or equivalent techniques. These texts include Ausubel et al.,Current Protocols in Molecular Biology, John Wiley and Sons, Inc.(2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3^(rd)edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000);Coligan et al., Current Protocols in Immunology, John Wiley & Sons,N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons,N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975),Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.,18^(th) edition (1990), Mandell, et al., Principles and Practice ofInfectious Diseases, Saunders Publishing (8th edition, 2014). Thesetexts can, of course, also be referred to in making or using an aspectof the disclosure.

As used herein, the term “combination therapy” or “co-therapy” includesthe administration of a compound of the present disclosure, or apharmaceutically acceptable salt, polymorph or solvate thereof, and atleast a second agent as part of a specific treatment regimen intended toprovide the beneficial effect from the co-action of these therapeuticagents. The beneficial effect of the combination includes, but is notlimited to, pharmacokinetic or pharmacodynamic co-action resulting fromthe combination of therapeutic agents.

It is to be understood that the present disclosure also providespharmaceutical compositions comprising any compound described herein incombination with at least one pharmaceutically acceptable excipient orcarrier.

As used herein, the term “pharmaceutical composition” is a formulationcontaining the compounds of the present disclosure in a form suitablefor administration to a subject. In one embodiment, the pharmaceuticalcomposition is in bulk or in unit dosage form. The unit dosage form isany of a variety of forms, including, for example, a capsule, an IV bag,a tablet, a single pump on an aerosol inhaler or a vial. The quantity ofactive ingredient (e.g., a formulation of the disclosed compound orsalt, hydrate, solvate or isomer thereof) in a unit dose of compositionis an effective amount and is varied according to the particulartreatment involved. One skilled in the art will appreciate that it issometimes necessary to make routine variations to the dosage dependingon the age and condition of the patient. The dosage will also depend onthe route of administration. A variety of routes are contemplated,including oral, pulmonary, rectal, parenteral, transdermal,subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational,buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.Dosage forms for the topical or transdermal administration of a compoundof this disclosure include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. In one embodiment, theactive compound is mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that are required.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, anions, cations, materials, compositions, carriers, and/ordosage forms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings and animalswithout excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

As used herein, the term “pharmaceutically acceptable excipient” meansan excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes excipient that is acceptable for veterinaryuse as well as human pharmaceutical use. A “pharmaceutically acceptableexcipient” as used in the specification and claims includes both one andmore than one such excipient.

It is to be understood that a pharmaceutical composition of thedisclosure is formulated to be compatible with its intended route ofadministration. Examples of routes of administration include parenteral,e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation),transdermal (topical), and transmucosal administration. Solutions orsuspensions used for parenteral, intradermal, or subcutaneousapplication can include the following components: a sterile diluent suchas water for injection, saline solution, fixed oils, polyethyleneglycols, glycerine, propylene glycol or other synthetic solvents;antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates, and agents for the adjustment of tonicity suchas sodium chloride or dextrose. The pH can be adjusted with acids orbases, such as hydrochloric acid or sodium hydroxide. The parenteralpreparation can be enclosed in ampoules, disposable syringes or multipledose vials made of glass or plastic.

It is to be understood that a compound or pharmaceutical composition ofthe disclosure can be administered to a subject in many of thewell-known methods currently used for chemotherapeutic treatment. Forexample, a compound of the disclosure may be injected into the bloodstream or body cavities or taken orally or applied through the skin withpatches. The dose chosen should be sufficient to constitute effectivetreatment but not so high as to cause unacceptable side effects. Thestate of the disease condition and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

As used herein, the term “therapeutically effective amount”, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician.

It is to be understood that, for any compound, the therapeuticallyeffective amount can be estimated initially either in cell cultureassays, e.g., of neoplastic cells, or in animal models, usually rats,mice, rabbits, dogs, or pigs. The animal model may also be used todetermine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic/prophylacticefficacy and toxicity may be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., ED₅₀ (thedose therapeutically effective in 50% of the population) and LD₅₀ (thedose lethal to 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index, and it can be expressed asthe ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit largetherapeutic indices are preferred. The dosage may vary within this rangedepending upon the dosage form employed, sensitivity of the patient, andthe route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compounds of thepresent disclosure may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol and sorbitol, and sodium chloridein the composition. Prolonged absorption of the injectable compositionscan be brought about by including in the composition an agent whichdelays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the disclosure are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the disclosure vary depending onthe agent, the age, weight, and clinical condition of the recipientpatient, and the experience and judgment of the clinician orpractitioner administering the therapy, among other factors affectingthe selected dosage. Generally, the dose should be sufficient to resultin slowing, and preferably regressing, the symptoms of the disease andalso preferably causing complete regression of the disease. Dosages canrange from about 0.01 mg/kg per day to about 5000 mg/kg per day. Inpreferred aspects, dosages can range from about 1 mg/kg per day to about1000 mg/kg per day. In an aspect, the dose will be in the range of about0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about0.1 mg to about 1 g/day, in single, divided, or continuous doses (whichdose may be adjusted for the patient's weight in kg, body surface areain m², and age in years). An effective amount of a pharmaceutical agentis that which provides an objectively identifiable improvement as notedby the clinician or other qualified observer. Improvement in survivaland growth indicates regression. As used herein, the term “dosageeffective manner” refers to amount of an active compound to produce thedesired biological effect in a subject or cell.

It is to be understood that the pharmaceutical compositions can beincluded in a container, pack, or dispenser together with instructionsfor administration.

It is to be understood that, for the compounds of the present disclosurebeing capable of further forming salts, all of these forms are alsocontemplated within the scope of the claimed disclosure.

As used herein, the term “pharmaceutically acceptable salts” refer toderivatives of the compounds of the present disclosure wherein theparent compound is modified by making acid or base salts thereof. Insome embodiments, the pharmaceutically acceptable salt of a compound(e.g., a β-lactam compound or probenecid described herein) is also aprodrug of the compound. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines, alkali or organic salts of acidic residues suchas carboxylic acids, and the like. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include, but are not limited to, those derived from inorganic andorganic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic,acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic,citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric,glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic,hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic,hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric,oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicylic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and thecommonly occurring amine acids, e.g., glycine, alanine, phenylalanine,arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present disclosure alsoencompasses salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like. In the salt form, it isunderstood that the ratio of the compound to the cation or anion of thesalt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or1:3.

It is to be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same salt.

As used herein, the term “prodrug” refers to any agent which, whenadministered to a mammal, is converted in whole or in part to a targetedcompound (e.g., a β-lactam compound or probenecid described herein). Insome embodiments, the prodrug of a compound (e.g., a β-lactam compoundor probenecid described herein) is also a pharmaceutically acceptablesalt of the compound.

It is to be understood that the compounds of the present disclosure canalso be prepared as esters, for example, pharmaceutically acceptableesters. For example, a carboxylic acid function group in a compound canbe converted to its corresponding ester, e.g., a methyl, ethyl or otherester. Also, an alcohol group in a compound can be converted to itscorresponding ester, e.g., acetate, propionate or other ester.

The compounds, or pharmaceutically acceptable salts thereof, areadministered orally, nasally, transdermally, pulmonary, inhalationally,buccally, sublingually, intraperitoneally, subcutaneously,intramuscularly, intravenously, rectally, intrapleurally, intrathecallyand parenterally. In one embodiment, the compound is administeredorally. One skilled in the art will recognize the advantages of certainroutes of administration.

The dosage regimen utilizing the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counter,or arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compoundsof the disclosure can be found in Remington: the Science and Practice ofPharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995). Inan embodiment, the compounds described herein, and the pharmaceuticallyacceptable salts thereof, are used in pharmaceutical preparations incombination with a pharmaceutically acceptable carrier or diluent.Suitable pharmaceutically acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present disclosure areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentdisclosure. The examples do not limit the claimed disclosure. Based onthe present disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the present disclosure.

In the synthetic schemes described herein, compounds may be drawn withone particular configuration for simplicity. Such particularconfigurations are not to be construed as limiting the disclosure to oneor another isomer, tautomer, regioisomer or stereoisomer, nor does itexclude mixtures of isomers, tautomers, regioisomers or stereoisomers;however, it will be understood that a given isomer, tautomer,regioisomer or stereoisomer may have a higher level of activity thananother isomer, tautomer, regioisomer or stereoisomer.

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules described herein for activity, using techniques known in theart. General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

As used herein, the term “granular material” refers to a conglomerationof discrete solid, macroscopic particles. In some embodiments, thegranular material is prepared by granulating a powdery or solidsubstance (e.g., a common granulation process in the art of chemical andpharmaceutical industry). In some embodiments, the granulation involvesagglomeration of fine particles into larger granules (e.g., granuleswith a size range between 0.2 mm and 4.0 mm). In some embodiments, thegranulation involves shredding or grinding solid material into finergranules or pellets.

As used herein, the term “friability” refers to the tendency of a solidsubstance to break into smaller pieces under duress or contact. In someembodiments, the friability is measured and quantified by commontechniques in the art. (e.g., by a method described in USP <1216>). Insome embodiments, the friability is measured by a method in which atransparent rotating drum is used and tablet weights taken before andafter tumbling.

As used herein, the term “total pore surface area” refers to the totalarea of the surface of the pores in an object (e.g., a bilayer tablet ofthe present disclosure). In some embodiments, the total pore surfacearea is measured by a common technique in the art (e.g., an X-rayComputed Tomography (X-ray CT)).

As used herein, the term “total pore count” refers to the total amountof the pores in an object (e.g., a bilayer tablet of the presentdisclosure). In some embodiments, the total pore count is measured by acommon technique in the art (e.g., an X-ray Computed Tomography (X-rayCT)).

As used herein, the term “largest pore volume” refers to the volume ofthe largest pore in an object (e.g., a bilayer tablet of the presentdisclosure). In some embodiments, the largest pore volume is measured bya common technique in the art (e.g., an X-ray Computed Tomography (X-rayCT)).

As used herein, the term “total pore volume” refers to the total volumeof all pores in an object (e.g., a bilayer tablet of the presentdisclosure). In some embodiments, the total pore volume is measured by acommon technique in the art (e.g., an X-ray Computed Tomography (X-rayCT)).

As used herein, the term “porosity” refers to a fraction of the volumeof void spaces in a material over the total volume of the material. Insome embodiments, the porosity is measured by a common technique in theart, e.g., an industrial CT scanning.

In some embodiments, the porosity is measured by X-ray ComputedTomography (X-ray CT). X-ray CT is a non-destructive analysis techniqueused to visualise and quantify the interior of a material in 3D. In anexemplary procedure, tablets were securely held in an X-ray transparentpolystyrene block during scanning. Tablets were scanned individuallyusing a GE V|TOME|X M 240 kV (GE Sensing and Inspection Technologies,Wunstorf, Germany) X-ray CT system. X-ray tube energy and current was 80kv and 160 μA, respectively. The scan consisted of 2400 radiographimages (each an integration of 8 images to reduce image noise) at aresolution of 14 microns. On data reconstruction a digital magnificationfactor was used to achieve a final resolution of 7.5 microns. Lowattenuating materials such as air (voids) appear as dark regions. Higherattenuating materials or denser regions in the sample appear brighter.Images, animations and microstructural quantification was performedusing Volume Graphics VGStudioMAX (v2.2) Software (Volume Graphics,GmbH, Germany).

As used herein, the term “comparable composition” refers to acomposition with comparable parameters, or in comparable conditions, asof the bilayer tablet of the present disclosure. In some embodiments,the comparable composition comprises the same amount of probenecid, orthe pharmaceutically acceptable salt thereof, and/or the β-lactamcompound, or the pharmaceutically acceptable salt thereof, as of thebilayer composition of the present disclosure. In some embodiments, thecomparable composition comprises probenecid, or the pharmaceuticallyacceptable salt thereof (e.g., a commercial composition of probenecid).In some embodiments, the comparable composition comprises the β-lactamcompound, or the pharmaceutically acceptable salt thereof (e.g., acommercial composition of Compound III-2b). In some embodiments, thecomparable composition comprises probenecid, or the pharmaceuticallyacceptable salt thereof, and the β-lactam compound, or thepharmaceutically acceptable salt thereof. In some embodiments, thecomparable composition is a comparable tablet, i.e., a tablet withcomparable parameters, or in comparable conditions, as of the bilayertablet of the present disclosure. In some embodiments, the comparabletablet comprises the same amount of probenecid, or the pharmaceuticallyacceptable salt thereof, and/or the β-lactam compound, or thepharmaceutically acceptable salt thereof, as of the bilayer tablet ofthe present disclosure. In some embodiments, the comparable tablet is asingle layer tablet comprising probenecid, or the pharmaceuticallyacceptable salt thereof (e.g., a commercial tablet of probenecid). Insome embodiments, the comparable tablet is a single layer tabletcomprising the β-lactam compound, or the pharmaceutically acceptablesalt thereof (e.g., a commercial tablet of Compound III-2b). In someembodiments, the comparable tablet is a single layer tablet comprisingprobenecid, or the pharmaceutically acceptable salt thereof, and theβ-lactam compound, or the pharmaceutically acceptable salt thereof. Insome embodiments, the comparable tablet is a bilayer tablet prepared bya different process as compared to the bilayer tablet of the presentdisclosure. In some embodiments, the comparable tablet is a bilayertablet prepared by a process with one or more different conditions(e.g., pressing sequence, the first force, and/or the second force) ascompared to the bilayer tablet of the present disclosure.

In some embodiments, the comparable composition is a suspension orsolution with comparable parameters, or in comparable conditions, as ofthe bilayer tablet of the present disclosure. In some embodiments, thecomparable suspension or solution comprises the same amount ofprobenecid, or the pharmaceutically acceptable salt thereof, and/or theβ-lactam compound, or the pharmaceutically acceptable salt thereof, asof the bilayer suspension or solution of the present disclosure. In someembodiments, the comparable suspension or solution comprises probenecid,or the pharmaceutically acceptable salt thereof (e.g., a commercialsuspension or solution of probenecid). In some embodiments, thecomparable suspension or solution comprises the β-lactam compound, orthe pharmaceutically acceptable salt thereof (e.g., a commercialsuspension or solution of Compound III-2b). In some embodiments, thecomparable suspension or solution comprises probenecid, or thepharmaceutically acceptable salt thereof, and the β-lactam compound, orthe pharmaceutically acceptable salt thereof.

In some embodiments, the comparable composition is a combination of theβ-lactam compound, or the pharmaceutically acceptable salt thereof, andprobenecid, or the pharmaceutically acceptable salt thereof, beingformulated in separate formulations that have comparable parameters, orare in comparable conditions, as of the bilayer tablet of the presentdisclosure. In some embodiments, the comparable composition is acombination of the β-lactam compound, or the pharmaceutically acceptablesalt thereof (e.g., Compound III-2b) formulated in a first comparabletablet, suspension, or solution, and probenecid, or the pharmaceuticallyacceptable salt thereof formulated in a second comparable tablet,suspension, or solution.

All publications and patent documents cited herein are incorporatedherein by reference as if each such publication or document wasspecifically and individually indicated to be incorporated herein byreference. Citation of publications and patent documents is not intendedas an admission that any is pertinent prior art, nor does it constituteany admission as to the contents or date of the same. The inventionhaving now been described by way of written description, those of skillin the art will recognize that the invention can be practiced in avariety of embodiments and that the foregoing description and examplesbelow are for purposes of illustration and not limitation of the claimsthat follow.

EXAMPLES Example 1. Preparation of the Bilayer Tablets

Various batches of bilayer tablets of the present disclosure comprising500 mg of probenecid and 500 mg of Compound III-2b are preparedaccording to the processes described in FIGS. 1-3 and to the processesdescribed herein.

Preparing Probenecid Bulk Granular Material.

The probenecid API and excipients (except magnesium stearate) are loadedinto a single pot wet granulator bowl and mixed. The granulationsolution (IPA:Water) is then added, with consistent impeller rotationand the chopper rotation. For wet massing the impeller is run until endpoint achieved (currently defined by time of run). The granule mass issubmitted to drying by vacuum and heat prior to granule screening in acone mill fitted with a suitable opening size rasping screen. Magnesiumstearate is added and lubrication takes place.

Preparing Compound III-2b Bulk Granular Material.

The Compound III-2b API is mixed with the excipients (except magnesiumstearate) in an IBC blender and is blended. Magnesium stearate is addedto the blend and intragranular lubrication performed. The lubricatedblend is dry granulated via one or more roller compactions to obtaincompacted ribbon sections. Within the same equipment, ribbons arepre-crushed and screened through suitable size screens. Magnesiumstearate is added and lubrication via blending takes place.

Preparing Bilayer Tablets.

A rotary tablet press fitted with D type oval die and punch sets is usedfor tablet compression of the Probenecid and Compound III-2b bulkgranules. The first bulk granular material is added and pre-compressedprior to addition of the second bulk granular material and finalcompression. Exemplary tablets are produced at the target weight of 1381mg and a target thickness 8.2 mm. Tablets are coated with Opadry® AMBWhite 80W68912 coating in a coating pan. The target coating weight gainis 4% w/w per tablet.

Composition and physical properties of the prepared tablets are shown inTables 1A and 1B below.

TABLE 1A Component Grade Function % w/w mg/tablet Compound III-2bgranular material Compound III-2b^(a) Pharm API 75.0 500.0Microcrystalline cellulose^(b) USP/NF/Ph. Eur. Filler 21.0 140.0Croscarmellose sodium USP/NF/Ph. Eur. Disintegrant 3.0 20.0Intragranular Magnesium Stearate NF/Ph. Eur. Lubricant 0.5 3.3Extragranular Magnesium Stearate NF/Ph. Eur. Lubricant 0.5 3.3 Layerweight 100 666.7 Probenecid granular material Probenecid^(a) Pharm API70 500.0 Microcrystalline cellulose^(b) USP/NF/Ph. Eur. Filler 11.9 85.0Lactose monohydrate 316 USP/NF/Ph. Eur. Filler 9.6 68.6Hydroxypropylcellulose USP/NF/Ph. Eur. Binder 3 21.4 Croscarmellosesodium NF/Ph. Eur. Disintegrant 5 35.7 Extragranular Magnesium StearateNF/Ph. Eur. Lubricant 0.5 3.6 Layer weight 100 714.3 Bilayer tabletBilayer tablet core weight 1.381 g Coating Opadry AMB Pharm Film Coat4.0 0.055 g Bilayer tablet weight 1.436 g ^(a)Assuming a potency of 100%^(b)Type PH102; the microcrystalline cellulose weight is adjustedaccording to correct for potency of the active drug substance.

TABLE 1B Property Value/Range/Description Tablet tensile 1.6-2.18 MPa(influenced by input granule strength/hardness property (TS) andcompression pressure) Tablet weight 1.36-1.40 g Tablet length 19 mmTablet width 10.3 mm Tablet thickness 8.0 - 8.4 mm Tablet friability<1.0% Ejection force <3 MPa across run Compression force 1.5 kN(0.5-11.5 kN) 1st layer Compression force 11.5 kN (1.5-30 kN) 2nd layer

In-Process Controls.

Loss on Drying is performed on probenecid granules to assure completedrying. Granule uniformity is performed on both probenecid and CompoundIII-2b granular materials. Throughout tablet manufacture, tablet weightuniformity, hardness, thickness, and friability are checked to assuretablets are produced at the target weight (single layer and tabletcore), thickness range, and suitable hardness for further processing. Inaddition, tablet cores for content uniformity are also collected atdefined intervals during process run. Coated tablets are inspected forappearance and weight gain, using AQL sampling. The acceptance criteriafor the in-process controls are summarized in Table 2 below.

TABLE 2 In process Control Acceptance criteria Probenecid Granule Stage1: RSD ≤ 3% w/w Uniformity if stage 1 not met, progress to stage 2testing Stage 2: RSD ≤ 5% w/w Probenecid Granule LOD LOD ≤ 3% w/wSulopenem etzadroxil Stage 1: RSD ≤ 3% w/w Granule Uniformity if stage 1not met, progress to stage 2 testing Stage 2: RSD ≤ 5% w/w 1st layerindividual weight Target: 714.3 mg (when Probenecid) Warning limits(±2.5%): 696.4-732.2 mg Action limits (±5%): 678.6-750.0 mg 1st layerindividual weight Target: 666.7 mg (when Sulopenem Warning limits(±2.5%): 650.0-683.4 mg etzadroxil) Action limits (±5%): 633.4-700.0 mg1st layer average weight (10 Target: 714.3 mg count) (when Probenecid)Warning limits (1.5%): 703.6-725.0 mg Action limits (±3%): 692.9 - 735.7mg 1st layer average weight (10 Target: 666.7 mg count) (when SulopenemWarning limits (±1.5%): 656.7-676.7 mg etzadroxil) Action limits (±3%):646.7-688.7 mg Individual tablet core weight Target: 1381 mg Warninglimits (±2.5%): 1346.5-1415.5 mg Action limits (±5%): 1312.0-1450.1 mgMean tablet core weight (10 Target: 1381 mg count) Warning limits(±1.5%): 1360.3-1401.7 mg Action limits (±3%): 1339.6-1422.4 mg TabletThickness Target: 8.2 mm; Range 8.0 to 8.4 mm Hardness Target: 150-250 NFriability (USP <1216>) NMT 1.0% w/w Tablet core content Compare allresults to ASTM E2709/E2810 uniformity tables for 90% confidence/95%probability of passing USP <905>for a sample size of n = 30 Coatedtablet Weight gain Target: 4% w/w Coated tablet Visual White tooff-white or pink colored oval shape Inspection tablet

Example 2. In Vitro Release Characteristics of the Bilayer Tablets

The in vitro release characteristics of bilayer tablets preparedaccording to the procedure described in Example 1 are tested using theUSP <711>-compliant method (with conditions shown in Table 3 below) andare analyzed by HPLC-UV (with the HPLC operating conditions shown inTable 4 below).

TABLE 3 Apparatus USP Apparatus II (Paddles) Media Temperature 37° C.Sampling Volume 2.5 mL Rotation Speed 75 RPM Media Volume 900 mLDissolution Media Phosphate Buffer pH 6.8 Sampling times 5, 10, 15, 20,30, 45 and 60 minutes

TABLE 4 Column Waters X-Select HSS C18, 30 mm × 3.0 mm i.d. 3.5 μm orequivalent Flow Rate 2.0 mL/min Column Temperature 30° C. InjectionVolume 20 μL Mobile Phase A 0.1% Formic Acid in Water Mobile Phase B0.1% Formic Acid in Acetonitrile Auto Sampler 5° C. TemperatureDetection UV 288 nm Run Time 5 minutes Gradient Time (min) % A % BGradient Type 0 95 5 Initial 3.3 5 95 Linear 3.4 95 5 Step 5.0 95 5 Re-equilibration

The detailed procedure for the test is described below.

Dissolution Media.

Accurately weigh 68 g of potassium dihydrogen phosphate into a 10 Lflask and dissolve with an appropriate volume of water. Make to 10 litertotal volume with water and mix well. Adjust to pH 6.8.

Standard Solution.

Accurately weigh 27.5 mg of Compound III-2b and 27.5 mg of probenecidreference standard into an amber 50 mL volumetric flask. Addapproximately 30 mL of dissolution media and sonicate the flask untilthe standards are completely dissolved. Dilute the flask to volume withdissolution media and mix well.

Test Procedures.

Set-up the dissolution bath according to Table 3. Transfer 900 mL ofdissolution media into each vessel and ensure the dissolution media isequilibrated to 37° C. Transfer a tablet into each vessel (N=6) andstart the dissolution. A volume of media (2.5 mL) is removed from thevessel at each specified time-point according to Table 3. The samplesolution is filtered and added to a HPLC vial for analysis against areference standard solution according to Table 4.

Calculations.

Calculate the response factor (RF) for Compound III-2b and probenecid inStandard:

${RF} = \frac{{AR} \times D}{{WR} \times P}$

where:

-   -   AR=Area of Compound III-2b or probenecid    -   WR=weight of Compound III-2b or probenecid standard (mg)    -   P=Purity of reference standard in decimal format (e.g.,        100.0%=1.00)    -   D=Dilution factor of standard

Calculate the content (mg) of Compound III-2b and probenecid dissolvedat each timepoint:

${C\; 1} = \left( \frac{A\; 1 \times V}{{RF}\mspace{11mu} {AVG}} \right)$$C = {\left( \frac{A\; 2 \times \left( {V - {PV}} \right)}{{RF}\mspace{11mu} {AVG}} \right) + \left( {C\; 1} \right)}$${C\; 3} = {\left( \frac{A\; 3 \times \left( {V - \left( {2 \times {PV}} \right)} \right)}{{RF}\mspace{11mu} {AVG}} \right) + \left( {{C\; 1} + {C\; 2}} \right)}$${C\; 4} = {\left( \frac{A\; 4 \times \left( {V - \left( {3 \times {PV}} \right)} \right)}{{RF}\mspace{11mu} {AVG}} \right) + \left( {{C\; 1} + {C\; 2} + {C\; 3}} \right)}$${C\; 5} = {\left( \frac{A\; 5 \times \left( {V - \left( {4 \times {PV}} \right)} \right)}{{RF}\mspace{11mu} {AVG}} \right) + \left( {{C\; 1} + {C\; 2} + {C\; 3} + {C\; 4}} \right)}$${C\; 6} = {\left( \frac{A\; 6 \times \left( {V - \left( {5 \times {PV}} \right)} \right)}{{RF}\mspace{11mu} {AVG}} \right) + \left( {{C\; 1} + {C\; 2} + {C\; 3} + {C\; 4} + {C\; 5}} \right)}$

where:

-   -   A_(n)=Peak area response of Compound III-2b or probenecid in the        sample at withdrawal point “n”    -   RF AVG=Average standard response factor for Compound III-2b or        probenecid from the bracketing standard of each sample    -   V=Initial volume of medium=900 mL    -   PV=Pull volume (mL)    -   C_(n)=Content (mg)

Calculate the percent of Compound III-2b and probenecid dissolved ateach time-point:

${\% \mspace{14mu} {Dissolved}\mspace{14mu} {at}\mspace{14mu} {each}\mspace{14mu} {timepoint}} = {\left( \frac{Cn}{LC} \right) \times (100)}$

where:

-   -   LC=Label Claim 500 mg for Compound III-2b and 500 mg for        probenecid    -   “C_(n)”=Content of Compound III-2b and probenecid (mg) at each        time-point

Method Validation.

The analysis by HPLC-UV has been validated. The parameters evaluated,acceptance criteria and results are presented in Table 5 and are incompliance with ICH Q2 requirements. The method is validated for itsintended purpose.

TABLE 5 Parameter Acceptance Criteria Result Specificity No interferingpeak > 1% in No interfering peak >1% in the elution zone of Compound theelution zone of Compound III-2b and probenecid III-2b and probenecidAccuracy The recovery at each level Compound III-2b should be within 95%to 50% = 96.5% 105% over a range from 50% 100% = 97.3% to 120% ofnominal 120% = 97.3% concentration Probenecid 50% = 104.4% 100% = 100.2%120% = 99.0% Precision % RSD <2.0% Compound III-2b % RSD = 0.2%Probenecid % RSD = 0.3% Filter The % Recoveries are Compound III-2bSuitability within 95%-105% 99.3%, 99.6% Probenecid 99.2%, 99.8%

Several exemplary batches of bilayer tablet are prepared with first andsecond compression forces shown in Table 6A. The in vitro releasecharacteristics of the exemplary batches of bilayer tablets are shown inTable 6B below and in FIGS. 4A-4D.

TABLE 6A First Compression Second Compression Force (kN) Force (kN)Batch No 1 0.94 13.12 Batch No 2 0.51 8.34 Batch No 3 2.12 12.65 BatchNo 4 2.77 15.51 Batch No 5 2.18 14.27 Batch No 6 2.56 13.22

TABLE 6B Batch No. 1 Batch No. 2 Batch No. 3 Released Released ReleasedSampling Compound Released Compound Released Compound Released Time(min) III-2b (%) Probenecid (%) III-2b (%) Probenecid (%) III-2b (%)Probenecid (%)  5 47 41 52 43 54 37 10 71 87 74 86 77 75 15 84 96 84 9887 96 20 92 97 89 100 93 97 30 100 97 95 101 98 98 45 102 97 96 101 10099 60 102 97 97 102 102 99 Batch No. 4 Batch No. 5 Batch No. 6 ReleasedReleased Released Sampling Compound Released Compound Released CompoundReleased Time (min) III-2b (%) Probenecid (%) III-2b (%) Probenecid (%)III-2b (%) Probenecid (%)  5 40 25 47 28 47 30 10 63 66 71 71 70 72 1574 92 82 94 81 94 20 80 99 89 98 87 98 30 87 100 95 100 93 99 45 91 10199 100 97 100 60 93 101 100 101 98 101

Example 3. Effects of Pressing Force on the Physical Properties of theBilayer Tablets

Bilayer tablets are prepared according to the procedure described inExample 1 and with various first and second pressing forces (shown inTable 7A below).

TABLE 7A Tablet Sample # First Force (kN) Second Force (kN) 1 1.50 11.502 11.50 1.50 3 1.25 30.00 4 2.00 20.00 5 1.25 15.00 6 0.50 10.00 7 1.255.00

The tables are characterized by X-ray Computed Tomography (X-ray CT) andthe collected data are subsequently quantified. X-ray ComputedTomography (X-ray CT). X-ray CT is a non-destructive analysis techniqueused to visualise and quantify the interior of a material in 3D. Tabletswere securely held in an X-ray transparent polystyrene block duringscanning. Tablets were scanned individually using a GE V|TOME|X M 240 kV(GE Sensing and Inspection Technologies, Wunstorf, Germany) X-ray CTsystem. X-ray tube energy and current was 80 kv and 160 μA,respectively. The scan consisted of 2400 radiograph images (each anintegration of 8 images to reduce image noise) at a resolution of 14microns. On data reconstruction a digital magnification factor was usedto achieve a final resolution of 7.5 microns. Low attenuating materialssuch as air (voids) appear as dark regions. Higher attenuating materialsor denser regions in the sample appear brighter. Images, animations andmicrostructural quantification was performed using Volume GraphicsVGStudioMAX (v2.2) Software (Volume Graphics, GmbH, Germany). Physicalcharacteristics of the tablets a shown in FIGS. 5A-5F. The in vitrorelease characteristics of an exemplary batch of bilayer tablets(prepared by first compression force at 2.06 kN and second compressionforce at 25.69 kN) are shown in FIG. 5G and Table 7B.

TABLE 7B Sampling Time Released Compound Released (min) III-2b (%)Probenecid (%) 5 36 19 10 60 50 15 72 77 20 79 93 30 86 98 45 91 99 6094 99

Example 4: Effects of Administrating β-Lactam Compounds and Probenecidby the Same Administration Route

Normal and healthy subjects were given the β-lactam compound (CompoundIII-2b; sulopenem etzadroxil) and probenecid in two separate studies. InStudy No. 1, subjects were administered 500 mg of sulopenem etzadroxilas a powder for oral suspension and simultaneously dosed with 500 mg ofprobenecid provided as a monolayer tablet. In Study No. 2, subjects wereadministered 500 mg of sulopenem etzadroxil with 500 mg of probenecid ina bilayer tablet. The results of the two studies are shown in FIGS. 6-9and Table 8 below.

TABLE 8 AUC_(last) ng · hr/ml Fasted Fed Study No. 1 4325.9 6592.8 StudyNo. 2 5099.5 7336.4 Difference (% Increase) 773.6 (17.9%) 743.6 (11.3%)

It is observed that administration of sulopenem etzadroxil andprobenecid in the bilayer tablet results in an increase in the amount ofsulopenem in the blood relative to dosing each agent in a separateformulation.

Administration in the fasted state of a combination of sulopenemetzadroxil and probenecid in the bilayer tablet results in a 17.9%increase in the amount of sulopenem in the blood, as measured by thearea under the curve, relative to the same amount of sulopenemetzadroxil delivered as powder in a bottle administered with probenecidin a monolayer tablet.

Similarly, the administration in the fed state of a combination ofsulopenem etzadroxil and probenecid in the bilayer tablet results in a11.3% increase in the amount of sulopenem in the blood, as measured bythe area under the curve, relative to the same amount of sulopenemetzadroxil delivered as powder in a bottle administered with probenecidin a monolayer tablet.

EQUIVALENTS

It is to be understood that the invention can be embodied in otherspecific forms without departing from the spirit or essentialcharacteristics thereof. The foregoing embodiments are therefore to beconsidered in all respects illustrative rather than limiting on theinvention described herein. Scope of the invention is thus indicated bythe appended claims rather than by the foregoing description, and allchanges that come within the meaning and range of equivalency of theclaims are intended to be embraced therein.

1. A bilayer tablet, comprising: a first layer comprising probenecid orthe pharmaceutically acceptable salt thereof; and a second layercomprising the β-lactam compound or the pharmaceutically acceptable saltthereof.
 2. The bilayer tablet of claim 1, wherein: the first layercomprises from 20 mg to about 5 g, from about 50 mg to about 2 g, fromabout 80 mg to about 1 g, from about 100 mg to about 900 mg, from about200 mg to about 800 mg, from about 300 mg to about 700 mg, from about400 mg to about 600 mg, from about 450 mg to about 550 mg, or from about480 mg to about 520 mg of probenecid or the pharmaceutically acceptablesalt thereof; and the second layer comprises from 20 mg to about 5 g,from about 50 mg to about 2 g, from about 80 mg to about 1 g, from about100 mg to about 900 mg, from about 200 mg to about 800 mg, from about300 mg to about 700 mg, from about 400 mg to about 600 mg, from about450 mg to about 550 mg, or from about 480 mg to about 520 mg of theβ-lactam compound or the pharmaceutically acceptable salt thereof. 3.The bilayer tablet of claim 1, wherein: the first layer comprises about500 mg of probenecid or the pharmaceutically acceptable salt thereof;and the second layer comprises about 500 mg of the β-lactam compound orthe pharmaceutically acceptable salt thereof. 4.-5. (canceled)
 6. Thebilayer tablet of claim 1, wherein the second layer comprises:


7. The bilayer tablet of claim 1, wherein the second layer comprisesCompound III-2b. 8.-9. (canceled)
 10. The bilayer tablet of claim 1,further comprising one or more of pharmaceutical excipients selectedfrom cellulose, sodium croscamellose, magnesium stearate, lactosemonohydrate, and hydroxypropylcellulose.
 11. (canceled)
 12. The bilayertablet of claim 1, further comprising: from about 220 mg to about 230 mgof microcrystalline cellulose; from about 50 mg to about 60 mg of sodiumcroscamellose; from about 3 mg to about 4 mg of intragranular magnesiumstearate; from about 6 mg to about 8 mg of extragranular magnesiumstearate; from about 65 mg to about 75 mg of lactose monohydrate 316;and from about 20 to about 23 mg of hydroxypropylcellulose. 13.-26.(canceled)
 27. The bilayer tablet of claim 1, being configured torelease: about 40±20%, about 40±18%, about 40±16%, about 40±14%, about40±12%, about 40±10%, about 40±9%, about 40±8%, about 40±7%, about40±6%, about 40±5%, about 40±4%, about 40±3%, about 40±2%, or about40±1% of the β-lactam compound or the pharmaceutically acceptable saltthereof in the bilayer tablet within about 5 minutes; about 63±20%,about 63±18%, about 63±16%, about 63±14%, about 63±12%, about 63±10%,about 63±9%, about 63±8%, about 63±7%, about 63±6%, about 63±5%, about63±4%, about 63±3%, about 63±2%, or about 63±1% of the β-lactam compoundor the pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes; about 74±10%, about 74±9%, about 74±8%, about74±7%, about 74±6%, about 74±5%, about 74±4%, about 74±3%, about 74±2%,or about 74±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 15 minutes;about 80±10%, about 80±9%, about 80±8%, about 80±7%, about 80±6%, about80±5%, about 80±4%, about 80±3%, about 80±2%, or about 80±1% of theβ-lactam compound or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 20 minutes; about 87±5%, about 87±4%, about87±3%, about 87±2%, or about 87±1% of the β-lactam compound or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 30 minutes; and about 91±5%, about 91±4%, about 91±3%, about91±2%, or about 91±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 45 minutes.28. The bilayer tablet of claim 1, being configured to release: about47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%,about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactamcompound or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes; about 71±20%, about 71±18%, about 71±16%,about 71±14%, about 71±12%, about 71±10%, about 71±9%, about 71±8%,about 71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about71±2%, or about 71±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 10 minutes;about 82±10%, about 82±9%, about 82±8%, about 82±7%, about 82±6%, about82±5%, about 82±4%, about 82±3%, about 82±2%, or about 82±1% of theβ-lactam compound or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 15 minutes; about 89±10%, about 89±9%, about89±8%, about 89±7%, about 89±6%, about 89±5%, about 89±4%, about 89±3%,about 89±2%, or about 89±1% of the β-lactam compound or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 20 minutes; and about 95±5%, about 95±4%, about 95±3%, about95±2%, or about 95±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 30 minutes.29. The bilayer tablet of claim 1, being configured to release: about47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%,about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactamcompound or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes; about 70±20%, about 70±18%, about 70±16%,about 70±14%, about 70±12%, about 70±10%, about 70±9%, about 70±8%,about 70±7%, about 70±6%, about 70±5%, about 70±4%, about 70±3%, about70±2%, or about 70±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 10 minutes;about 81±10%, about 81±9%, about 81±8%, about 81±7%, about 81±6%, about81±5%, about 81±4%, about 81±3%, about 81±2%, or about 81±1% of theβ-lactam compound or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 15 minutes; about 87±10%, about 87±9%, about87±8%, about 87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%,about 87±2%, or about 87±1% of the β-lactam compound or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 20 minutes; and about 93±5%, about 93±4%, about 93±3%, about93±2%, or about 93±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 30 minutes.30. The bilayer tablet of claim 1, being configured to release: about47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%,about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactamcompound or the pharmaceutically acceptable salt thereof in the bilayertablet within about 5 minutes; about 71±20%, about 71±18%, about 71±16%,about 71±14%, about 71±12%, about 71±10%, about 71±9%, about 71±8%,about 71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about71±2%, or about 71±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 10 minutes;about 84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about84±5%, about 84±4%, about 84±3%, about 84±2%, or about 84±1% of theβ-lactam compound or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 15 minutes; and about 92±10%, about 92±9%,about 92±8%, about 92±7%, about 92±6%, about 92±5%, about 92±4%, about92±3%, about 92±2%, or about 92±1% of the β-lactam compound or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 20 minutes.
 31. The bilayer tablet of claim 1, being configured torelease: about 52±20%, about 52±18%, about 52±16%, about 52±14%, about52±12%, about 52±10%, about 52±9%, about 52±8%, about 52±7%, about52±6%, about 52±5%, about 52±4%, about 52±3%, about 52±2%, or about52±1% of the β-lactam compound or the pharmaceutically acceptable saltthereof in the bilayer tablet within about 5 minutes; about 74±20%,about 74±18%, about 74±16%, about 74±14%, about 74±12%, about 74±10%,about 74±9%, about 74±8%, about 74±7%, about 74±6%, about 74±5%, about74±4%, about 74±3%, about 74±2%, or about 74±1% of the β-lactam compoundor the pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes; about 84±10%, about 84±9%, about 84±8%, about84±7%, about 84±6%, about 84±5%, about 84±4%, about 84±3%, about 84±2%,or about 84±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 15 minutes;about 89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about89±5%, about 89±4%, about 89±3%, about 89±2%, or about 89±1% of theβ-lactam compound or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 20 minutes; and about 95±5%, about 95±4%,about 95±3%, about 95±2%, or about 95±1% of the β-lactam compound or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 30 minutes.
 32. The bilayer tablet of claim 1, being configured torelease: about 53±20%, about 53±18%, about 53±16%, about 53±14%, about53±12%, about 53±10%, about 53±9%, about 53±8%, about 53±7%, about53±6%, about 53±5%, about 53±4%, about 53±3%, about 53±2%, or about53±1% of the β-lactam compound or the pharmaceutically acceptable saltthereof in the bilayer tablet within about 5 minutes; about 77±20%,about 77±18%, about 77±16%, about 77±14%, about 77±12%, about 77±10%,about 77±9%, about 77±8%, about 77±7%, about 77±6%, about 77±5%, about77±4%, about 77±3%, about 77±2%, or about 77±1% of the β-lactam compoundor the pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 10 minutes; about 87±10%, about 87±9%, about 87±8%, about87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%,or about 87±1% of the β-lactam compound or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 15 minutes;about 93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% ofthe β-lactam compound or the pharmaceutically acceptable salt thereof inthe bilayer tablet within about 20 minutes; and about 98±2%, about98±1.8%, about 98±1.6%, about 98±1.4%, about 98±1.2%, about 98±1%, about98±0.9%, about 98±0.8%, about 98±0.7%, about 98±0.6%, about 98±0.5%,about 98±0.4%, about 98±0.3%, about 98±0.2%, or about 98±0.1% of theβ-lactam compound or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 30 minutes.
 33. The bilayer tablet of claim1, being configured to release: about 25±10%, about 25±9%, about 25±8%,about 25±7%, about 25±6%, about 25±5%, about 25±4%, about 25±3%, about25±2%, or about 25±1% of probenecid or the pharmaceutically acceptablesalt thereof in the bilayer tablet within about 5 minutes; about 66±10%,about 66±9%, about 66±8%, about 66±7%, about 66±6%, about 66±5%, about66±4%, about 66±3%, about 66±2%, or about 66±1% of probenecid or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 10 minutes; and about 92±2%, about 92±1.8%, about 92±1.6%, about92±1.4%, about 92±1.2%, about 92±1%, about 92±0.9%, about 92±0.8%, about92±0.7%, about 92±0.6%, about 92±0.5%, about 92±0.4%, about 92±0.3%,about 92±0.2%, or about 92±0.1% of probenecid or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 15 minutes.34. The bilayer tablet of claim 1, being configured to release: about28±10%, about 28±9%, about 28±8%, about 28±7%, about 28±6%, about 28±5%,about 28±4%, about 28±3%, about 28±2%, or about 28±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes; about 71±10%, about 71±9%, about 71±8%, about71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about 71±2%,or about 71±1% of probenecid or the pharmaceutically acceptable saltthereof in the bilayer tablet within about 10 minutes; and about 94±2%,about 94±1.8%, about 94±1.6%, about 94±1.4%, about 94±1.2%, about 94±1%,about 94±0.9%, about 94±0.8%, about 94±0.7%, about 94±0.6%, about94±0.5%, about 94±0.4%, about 94±0.3%, about 94±0.2%, or about 94±0.1%of probenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 15 minutes.
 35. The bilayer tablet of claim1, being configured to release: about 30±10%, about 30±9%, about 30±8%,about 30±7%, about 30±6%, about 30±5%, about 30±4%, about 30±3%, about30±2%, or about 30±1% of probenecid or the pharmaceutically acceptablesalt thereof in the bilayer tablet within about 5 minutes; about 72±10%,about 72±9%, about 72±8%, about 72±7%, about 72±6%, about 72±5%, about72±4%, about 72±3%, about 72±2%, or about 72±1% of probenecid or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 10 minutes; and about 94±2%, about 94±1.8%, about 94±1.6%, about94±1.4%, about 94±1.2%, about 94±1%, about 94±0.9%, about 94±0.8%, about94±0.7%, about 94±0.6%, about 94±0.5%, about 94±0.4%, about 94±0.3%,about 94±0.2%, or about 94±0.1% of probenecid or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 15 minutes.36. The bilayer tablet of claim 1, being configured to release: about41±10%, about 41±9%, about 41±8%, about 41±7%, about 41±6%, about 41±5%,about 41±4%, about 41±3%, about 41±2%, or about 41±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes; about 87±10%, about 87±9%, about 87±8%, about87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%,or about 87±1% of probenecid or the pharmaceutically acceptable saltthereof in the bilayer tablet within about 10 minutes; and about 96±2%,about 96±1.8%, about 96±1.6%, about 96±1.4%, about 96±1.2%, about 96±1%,about 96±0.9%, about 96±0.8%, about 96±0.7%, about 96±0.6%, about96±0.5%, about 96±0.4%, about 96±0.3%, about 96±0.2%, or about 96±0.1%of probenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 15 minutes.
 37. The bilayer tablet of claim1, being configured to release: about 43±10%, about 43±9%, about 43±8%,about 43±7%, about 43±6%, about 43±5%, about 43±4%, about 43±3%, about43±2%, or about 43±1% of probenecid or the pharmaceutically acceptablesalt thereof in the bilayer tablet within about 5 minutes; about 86±10%,about 86±9%, about 86±8%, about 86±7%, about 86±6%, about 86±5%, about86±4%, about 86±3%, about 86±2%, or about 86±1% of probenecid or thepharmaceutically acceptable salt thereof in the bilayer tablet withinabout 10 minutes; and about 98±2%, about 98±1.8%, about 98±1.6%, about98±1.4%, about 98±1.2%, about 98±1%, about 98±0.9%, about 98±0.8%, about98±0.7%, about 98±0.6%, about 98±0.5%, about 98±0.4%, about 98±0.3%,about 98±0.2%, or about 98±0.1% of probenecid or the pharmaceuticallyacceptable salt thereof in the bilayer tablet within about 15 minutes.38. The bilayer tablet of claim 1, being configured to release: about37±10%, about 37±9%, about 37±8%, about 37±7%, about 37±6%, about 37±5%,about 37±4%, about 37±3%, about 37±2%, or about 37±1% of probenecid orthe pharmaceutically acceptable salt thereof in the bilayer tabletwithin about 5 minutes; about 75±10%, about 75±9%, about 75±8%, about75±7%, about 75±6%, about 75±5%, about 75±4%, about 75±3%, about 75±2%,or about 75±1% of probenecid or the pharmaceutically acceptable saltthereof in the bilayer tablet within about 10 minutes; and about 96±2%,about 96±1.8%, about 96±1.6%, about 96±1.4%, about 96±1.2%, about 96±1%,about 96±0.9%, about 96±0.8%, about 96±0.7%, about 96±0.6%, about96±0.5%, about 96±0.4%, about 96±0.3%, about 96±0.2%, or about 96±0.1%of probenecid or the pharmaceutically acceptable salt thereof in thebilayer tablet within about 15 minutes.
 39. A method of preparing abilayer tablet, comprising: i) compressing a first granular materialcomprising probenecid or a pharmaceutically acceptable salt thereof witha first force, thereby forming a pre-compressed first layer; ii) addinga second granular material comprising a β-lactam compound or apharmaceutically acceptable salt thereof to the pre-compressed firstlayer; iii) compressing the pre-compressed first layer and the secondgranular material with a second force, thereby forming a pre-coatedbilayer tablet. 40.-59. (canceled)
 60. A method of treating orpreventing a disease, comprising administering to a subject in needthereof a pharmaceutically effective amount of a bilayer tabletcomprising: a first layer comprising probenecid or the pharmaceuticallyacceptable salt thereof; and a second layer comprising the β-lactamcompound or the pharmaceutically acceptable salt thereof. 61.-81.(canceled)
 82. The bilayer tablet of claim 1, wherein the administrationresults in a plasma concentration for the β-lactam compound having: anarea under the curve (AUC) that is higher in the subject in need thereofas compared to a comparable subject being administered with a comparablecomposition by about 5% or greater, about 10% or greater, about 15% orgreater, about 20% or greater, about 25% or greater, about 30% orgreater, about 40% or greater, about 50% or greater, about 60% orgreater, about 80% or greater, about 100% or greater, about 150% orgreater, about 200% or greater, about 300% or greater, about 400% orgreater, or about 500% or greater within about 30 minutes, about 1 hour,about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, or about 7 days from the administration; and amaximum plasma concentration (C_(max)) in the subject in need thereofthat is from about 50% to about 150%, from about 60% to about 140%, fromabout 70% to about 130%, from about 80% to about 120%, from about 90% toabout 110%, from about 95% to about 105%, or from 98% to about 102% ascompared to a comparable subject being administered with a comparablecomposition. 83.-86. (canceled)
 87. The bilayer tablet of claim 1,wherein the administration results in a plasma concentration for theβ-lactam compound having: an area under the curve (AUC) being from about4325±3000 ng·h/mL, about 4325±2500 ng·h/mL, about 4325±2000 ng·h/mL,about 4325±1500 ng·h/mL, about 4325±1000 ng·h/mL, about 4325±900ng·h/mL, about 4325±800 ng·h/mL, about 4325±700 ng·h/mL, about 4325±600ng·h/mL, about 4325±500 ng·h/mL, about 4325±400 ng·h/mL, about 4325±300ng·h/mL, about 4325±200 ng·h/mL, about 4325±100 ng·h/mL, about 4325±90ng·h/mL, about 4325±80 ng·h/mL, about 4325±70 ng·h/mL, about 4325±60ng·h/mL, about 4325±50 ng·h/mL, about 4325±40 ng·h/mL, about 4325±30ng·h/mL, about 4325±20 ng·h/mL, or about 4325±10 ng·h/mL within about 1day from the administration.
 88. The bilayer tablet of claim 1, whereinthe bilayer tablet is administered to the subject in need thereof withfood, and the administration results in a plasma concentration for theβ-lactam compound having: an area under the curve (AUC) being from about6600±3000 ng·h/mL, about 6600±2500 ng·h/mL, about 6600±2000 ng·h/mL,about 6600±1500 ng·h/mL, about 6600±1000 ng·h/mL, about 6600±900ng·h/mL, about 6600±800 ng·h/mL, about 6600±700 ng·h/mL, about 6600±600ng·h/mL, about 6600±500 ng·h/mL, about 6600±400 ng·h/mL, about 6600±300ng·h/mL, about 6600±200 ng·h/mL, about 6600±100 ng·h/mL, about 6600±90ng·h/mL, about 6600±80 ng·h/mL, about 6600±70 ng·h/mL, about 6600±60ng·h/mL, about 6600±50 ng·h/mL, about 6600±40 ng·h/mL, about 6600±30ng·h/mL, about 6600±20 ng·h/mL, or about 6600±10 ng·h/mL within about 1day from the administration.
 89. The bilayer tablet of claim 1, whereinthe administration results in a plasma concentration for the β-lactamcompound having: an area under the curve (AUC) being from about5100±3000 ng·h/mL, about 5100±2500 ng·h/mL, about 5100±2000 ng·h/mL,about 5100±1500 ng·h/mL, about 5100±1000 ng·h/mL, about 5100±900ng·h/mL, about 5100±800 ng·h/mL, about 5100±700 ng·h/mL, about 5100±600ng·h/mL, about 5100±500 ng·h/mL, about 5100±400 ng·h/mL, about 5100±300ng·h/mL, about 5100±200 ng·h/mL, about 5100±100 ng·h/mL, about 5100±90ng·h/mL, about 5100±80 ng·h/mL, about 5100±70 ng·h/mL, about 5100±60ng·h/mL, about 5100±50 ng·h/mL, about 5100±40 ng·h/mL, about 5100±30ng·h/mL, about 5100±20 ng·h/mL, or about 5100±10 ng·h/mL within about 1day from the administration.
 90. The bilayer tablet of claim 1, whereinthe bilayer tablet is administered to the subject in need thereof withfood, and the administration results in a plasma concentration for theβ-lactam compound having: an area under the curve (AUC) being from about7340±3000 ng·h/mL, about 7340±2500 ng·h/mL, about 7340±2000 ng·h/mL,about 7340±1500 ng·h/mL, about 7340±1000 ng·h/mL, about 7340±900ng·h/mL, about 7340±800 ng·h/mL, about 7340±700 ng·h/mL, about 7340±600ng·h/mL, about 7340±500 ng·h/mL, about 7340±400 ng·h/mL, about 7340±300ng·h/mL, about 7340±200 ng·h/mL, about 7340±100 ng·h/mL, about 7340±90ng·h/mL, about 7340±80 ng·h/mL, about 7340±70 ng·h/mL, about 7340±60ng·h/mL, about 7340±50 ng·h/mL, about 7340±40 ng·h/mL, about 7340±30ng·h/mL, about 7340±20 ng·h/mL, or about 7340±10 ng·h/mL within about 1day from the administration.